Isoxazolines as inhibitors of fatty acid amide hydrolase

ABSTRACT

The present invention provides isoxazoline FAAH inhibitors of the formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable forms thereof, wherein each of G, R a , R b , R c , and R d  are as defined herein. 
           
         
       
    
     The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. 
     The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional patentapplication Ser. No. 61/179,280 filed May 18, 2009, the entirety ofwhich is hereby incorporated herein by reference.

BACKGROUND

Fatty acid amide hydrolase (FAAH), also referred to as oleamidehydrolase and anandamide amidohydrolase, is an integral membrane proteinresponsible for the hydrolysis of several important endogenousneuromodulating fatty acid amides (FAAs), including anadamide,oleoylethanolamide and palmitoylethanolamide, and is intimately involvedin their regulation. Because these FAAs interact with cannabinoid andvanilliod receptors, they are often referred to as “endocannabinoids” or“endovanilliods”. Initial interest in this area focused on developingFAAH inhibitors to augment the actions of FAAs and reduce pain. Furtherinvestigation found FAAH inhibitors, through interactions of the FAAswith unique extracellular and intracellular receptors, can be used totreat a variety of conditions that include, but are not limited to,inflammation, metabolic disorders (e.g., obesity-related conditions andwasting conditions such as cachexias and anorexia), disorders of thecentral nervous system (e.g., disorders associated with neurotoxicityand/or neurotrauma, stroke, multiple sclerosis, spinal cord injury,movement disorders such as basal ganglia disorders, amylotrophic lateralsclerosis, Alzheimer's disease, epilepsy, mental disorders such asanxiety, depression, learning disorders and Schizophrenia, sleepdisorders such as insomnia, nausea and/or emesis, and drug addiction),cardiac disorders (e.g., hypertention, circulatory shock, myocardialreperfusion injury and atherosclerosis) and glaucoma (Pacher et al.,“The Endocannabinoid System as an Emerging Target of Pharmacotherapy”Pharmacological Reviews (2006) 58:389-462; Pillarisetti et al., “Painand Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitorsin Cardiovascular and Metabolic Diseases” Drug Discovery Today (2009)597:1-14).

SUMMARY

The present invention provides isoxazoline FAAH inhibitor compounds ofthe formula (I):

or pharmaceutically acceptable forms thereof,

wherein:

each of R^(a), R^(b), and R^(c) independently is selected from H, C₁₋₁₀alkyl and C₁₋₁₀ perhaloalkyl, R^(d) is the group -L-Z, and Z is selectedfrom C₆₋₁₄ aryl;

L is a covalent bond or a divalent C₁₋₆ hydrocarbon group, wherein one,two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen, sulfur or nitrogen atoms;

G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —Br, —I, —F, —C1, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion;

each R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and 5-14membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

The present invention also provides pharmaceutical compositionscomprising a compound of formula (I), or a pharmaceutically acceptableform thereof, and a pharmaceutically acceptable excipient.

The present invention also provides methods for treating anFAAH-mediated condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable form thereof, to a subject in need thereof.

The details of additional embodiments of the invention are set forth inthe accompanying Detailed Description and Exemplification as describedbelow. Other features, objects, and advantages of the invention will beapparent from this description and from the claims.

DEFINITIONS

Definitions of specific functional groups ad chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds of the present invention can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds of the invention are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to compositions inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer in a control mixture of the racemic composition(e.g., greater than 1:1 by weight). For example, an enantiomericallyenriched preparation of the (S)-enantiomer, means a preparation of thecompound having greater than 50% by weight of the (S)-enantiomerrelative to the (R)-enantiomer, more preferably at least 75% by weight,and even more preferably at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” preparation,which refers to preparations of compositions which have at least 85% byweight of one enantiomer relative to other enantiomer, more preferablyat least 90% by weight, and even more preferably at least 95% by weight.In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub—range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein a “direct bond” or “covalent bond” refers to a singlebond joining two groups.

As used herein, alone or as part of another group, “halo” and “halogen”refer to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), or iodine (iodo, —I).

As used herein, alone or as part of another group, “alkyl” refers to amonoradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In some embodiments,an alkyl group has 1 to 9 carbon atoms (“C₁₋₉ alkyl”). In someembodiments, an alkyl group has 1 to 8 carbon atoms (“C₁₋₈ alkyl”). Insome embodiments, an alkyl group has 1 to 7 carbon atoms (“C₁₋₇ alkyl”).In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyunsubstituted (an “unsubstituted alkyl”) or substituted (a “substitutedalkyl”) are substituted with 1, 2, 3, 4, or 5 substituents as describedherein. In certain embodiments, the alkyl group is an unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group is asubstituted C₁₋₁₀ alkyl.

“Perhaloalkyl” as defined herein refers to an alkyl group having from 1to 10 carbon atoms wherein all of the hydrogen atoms are eachindependently replaced halogen, e.g., selected from fluoro, bromo,chloro or iodo (“C₁₋₁₀ perhaloalkyl”). In some embodiments, the alkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbonatoms (“C₁₋₄ perhaloalkyl”). In some embodiments, the alkyl moiety has 1to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In some embodiments, the alkylmoiety has 1 to 2 carbon atoms (“C₁₋₂ perhaloalkyl”). In someembodiments, all of the hydrogen atoms are each replaced with fluoro. Insome embodiments, all of the hydrogen atoms are each replaced withchloro. Examples of perhaloalkyl groups include —CF₃, —CF₂CF₃,—CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

As used herein, alone or as part of another group, “alkenyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 10 carbon atoms and one or more carbon-carbon double bonds(“C₂₋₁₀ alkenyl”). In some embodiments, an alkenyl group has 2 to 9carbon atoms (“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has2 to 8 carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenylgroup has 2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, analkenyl group has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In someembodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”).In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms(“C₂₋₃ alkenyl”). In some embodiments, an alkenyl group has 2 carbonatoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can beinternal (such as in 2-butenyl) or terminal (such as in 1-butenyl).Examples of C₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃),2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and thelike. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆)and the like. Additional examples of alkenyl include heptenyl (C₇),octenyl (C₈), octatrienyl (C₈) and the like. Unless otherwise specified,each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with1, 2, 3, 4, or 5 substituents as described herein. In certainembodiments, the alkenyl group is an unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is a substituted C₂₋₁₀ alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 10 carbon atoms and one or more carbon-carbon triple bonds(“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 9carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynylgroup has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, analkynyl group has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In someembodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”).In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms(“C₂₋₃ alkynyl”). In some embodiments, an alkynyl group has 2 carbonatom (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄)and the like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆) and the like.Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈) andthe like. Unless otherwise specified, each instance of an alkynyl groupis independently unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with 1, 2, 3, 4, or 5 substituentsas described herein. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

A “divalent C₁₋₆ hydrocarbon group” is a divalent C₁₋₆ alkyl group,divalent C₁₋₆ alkenyl group or divalent C₁ alkynyl group wherein one,two or three methylene units (—CH₂—) of the hydrocarbon chain areoptionally and independently replaced with one or more oxygen, sulfur ornitrogen atoms. In certain embodiments, the divalent C₁₋₆ hydrocarbongroup is a divalent C₁₋₆ alkyl group. In certain embodiments, thedivalent C₁₋₆ hydrocarbon group is an unsubstituted divalent C₁₋₆hydrocarbon group (e.g., an unsubstituted divalent C₁₋₆ alkyl group).

As used herein, alone or as part of another group, “alkoxy” refers to analkyl group, as defined herein, substituted with an oxygen atom, whereinthe point of attachment is the oxygen atom. In certain embodiments, thealkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkoxy”). In someembodiments, the alkyl group has 1 to 8 carbon atoms (“C₁₋₈ alkoxy”). Insome embodiments, the alkyl group has 1 to 6 carbon atoms (“C₁₋₆alkoxy”). In some embodiments, the alkyl group has 1 to 4 carbon atoms(“C₁₋₄ alkoxy”). Examples of C₁₋₄ alkoxy groups include methoxy (C₁),ethoxy (C₂), propoxy (C₃), isopropoxy (C₃), butoxy (C₄), tert-butoxy(C₅) and the like. Examples of C₁₋₆ alkoxy groups include theaforementioned C₁₋₄ alkoxy groups as well as pentyloxy (C₅),isopentyloxy (C₅), neopentyloxy (C₅), hexyloxy (C₆) and the like.Additional examples of alkoxy groups include heptyloxy (C₇), octyloxy(C₈) and the like. Unless otherwise specified, each instance of thealkyl moiety of the alkoxy group is independently unsubstituted (an“unsubstituted alkoxy”) or substituted (a “substituted alkoxy”) aresubstituted with 1, 2, 3, 4, or 5 substituents as described herein. Incertain embodiments, the alkoxy group is an unsubstituted C₂₋₁₀ alkoxy(e.g., —OCH₃). In certain embodiments, the alkoxy group is a substitutedC₂₋₁₀ alkoxy (e.g., perhaloalkoxy as defined herein).

“Perhaloalkoxy” refers to an alkoxy group wherein the all the hydrogenatoms of the alkyl moiety are each independently replaced with halogenatoms selected from fluoro, chloro, bromo and iodo. In certainembodiments, the alkyl moiety has 1 to 10 carbon atoms (“C₁₋₁₀perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 8 carbonatoms (“C₁₋₈ perhaloalkoxy”). In some embodiments, the alkyl moiety has1 to 6 carbon atoms (“C₁₋₆ perhaloalkoxy”). In some embodiments, thealkyl moiety has 1 to 4 carbon atoms (“C₁₋₄ perhaloalkoxy”). In someembodiments, the alkyl moiety has 1 to 3 carbon atoms (“C₁₋₃perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 2 carbonatoms (“C₁₋₂ perhaloalkoxy”). In some embodiments, all of the hydrogenatoms are each replaced with fluoro. In some embodiments, all of thehydrogen atoms are each replaced with chloro. Examples of perhaloalkoxygroups include, but are not limited to, —OCF₃, —OCF₂CF₃, —OCF₂CF₂CF₃,—OCCl₃, —OCFCl₂, —OCF₂Cl and the like.

As used herein, alone or as part of another group, “carbocyclyl” refersto a radical of a non-aromatic cyclic hydrocarbon group having from 3 to10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in thenon-aromatic ring system. In some embodiments, a carbocyclyl group has 3to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms(“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”). Examples of C₃₋₆ carbocyclylgroups include, without limitation, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆) and the like. Examples of C₃₋₈ carbocyclylgroups include the aforementioned C₃₋₆ carbocyclyl groups as well ascycloheptyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and thelike. Examples of C₃₋₁₀ carbocyclyl groups include the aforementionedC₃₋₈ carbocyclyl groups as well as octahydro-1H-indenyl,decahydronaphthalenyl, spiro[4.5]decanyl and the like. As the foregoingexamples illustrate, in certain embodiments, the carbocyclyl group iseither monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g.,containing a fused, bridged or spiro ring system such as a bicyclicsystem (“bicyclic carbocyclyl”) or tricyclic system (“tricycliccarbocyclyl”)) and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused withone or more aryl or heteroaryl groups wherein the point of attachment ison the carbocyclyl ring. Unless otherwise specified, each instance of acarbocyclyl group is independently unsubstituted (an “unsubstitutedcarbocyclyl”) or substituted (a “substituted carbocyclyl”) with 1, 2, 3,4, or 5 substituents as described herein. In certain embodiments, thecarbocyclyl group is an unsubstituted C₃₋₁₀ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with 1, 2, 3, 4, or 5 substituents asdescribed herein. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₀ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₀ cycloalkyl.

As used herein, alone or as part of another group, “heterocyclyl” refersto a radical of a 3- to 14-membered non-aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“3-14 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) ortricyclic system (“tricyclic heterocyclyl”)), and can be saturated orcan contain one or more carbon-carbon double or triple bonds.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. “Heterocyclyl” also includes ring systems whereinthe heterocycyl ring, as defined above, is fused with one or morecarbocycyl groups wherein the point of attachment is either on thecarbocycyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring. In some embodiments, a heterocyclyl group is a 5-10membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen and sulfur.Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. Unless otherwisespecified, each instance of heterocyclyl is independently unsubstituted(an “unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with 1, 2, 3, 4, or 5 substituents as described herein.In certain embodiments, the heterocyclyl group is an unsubstituted 3-14membered heterocyclyl. In certain embodiments, the heterocyclyl group isa substituted 3-14 membered heterocyclyl.

As used herein, alone or as part of another group, “aryl” refers to aradical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic)aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in acyclic array) having 6-14 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₄ aryl”). In someembodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In someembodiments, an aryl group has 14 ring carbon atoms (“C₁₋₄ aryl”; e.g.,anthracyl). “Aryl” also includes ring systems wherein the aryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the radical or point of attachment is on the aryl ring.Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with 1, 2, 3, 4, or 5 substituents as describedherein. In certain embodiments, the aryl group is an unsubstituted C₆₋₁₄aryl. In certain embodiments, the aryl group is a substituted C₆₋₁₄aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by an aryl group, as defined herein, whereinthe point of attachment is on the alkyl moiety.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclicor tricyclic) aromatic ring system (e.g., having 6, 10 or 14 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-14 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl polycyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” also includesring systems wherein the heteroaryl ring, as defined above, is fusedwith one or more aryl groups wherein the point of attachment is eitheron the aryl or on the heteroaryl ring, or wherein the heteroaryl ring,as defined above, is fused with one or more carbocycyl or heterocycylgroups wherein the point of attachment is on the heteroaryl ring. Forpolycyclic heteroaryl groups wherein one ring does not contain aheteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) thepoint of attachment can be on either ring, i.e., either the ring bearinga heteroatom (e.g., 2-indolyl) or the ring that does not contain aheteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group isa 5-10 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-6 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-6 membered heteroaryl”). In some embodiments, the 5-6 memberedheteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen andsulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ringheteroatoms selected from nitrogen, oxygen and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen and sulfur. Exemplary 5-membered heteroarylscontaining 1 heteroatom include, without limitation, pyrrolyl, furanyland thiophenyl. Exemplary 5-membered heteroaryls containing 2heteroatoms include, without limitation, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-memberedheteroaryls containing 3 heteroatoms include, without limitation,triazolyl, oxadiazolyl, thiadiazolyl. Exemplary 5-membered heteroarylscontaining 4 heteroatoms include, without limitation, tetrazolyl.Exemplary 6-membered heteroaryls containing 1 heteroatom include,without limitation, pyridinyl. Exemplary 6-membered heteroarylscontaining 2 heteroatoms include, without limitation, pyridazinyl,pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryls containing 3or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7 membered heteroaryls containing 1 heteroatominclude, without limitation, azepinyl, oxepinyl and thiepinyl. Exemplary5,6-bicyclic heteroaryls include, without limitation, indolyl,isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary6,6-bicyclic heteroaryls include, without limitation, naphthyridinyl,pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl,phthalazinyl and quinazolinyl. Exemplary tricyclic heteroaryls include,without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl,acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. Unless otherwisespecified, each instance of a heteroaryl group is independentlyunsubstituted (an “unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with 1, 2, 3, 4, or 5 substituents asdescribed herein. In certain embodiments, the heteroaryl group is anunsubstituted 5-14 membered heteroaryl. In certain embodiments, theheteroaryl group is a substituted 5-14 membered heteroaryl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by a heteroaryl group, as defined herein,wherein the point of attachment is on the alkyl moiety.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl moieties) as herein defined.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom etc.)is replaced with a permissible substituent, e.g., a substituent whichupon substitution results in a stable compound, e.g., a compound whichdoes not spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position.

Exemplary carbon atom substituents include, but are not limited to,halogen (i.e., fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I)),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂, —N(R^(bb))₂,—N(R^(bb))₃ ^(+X) ⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa), —SSR^(cc),—C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(S)SR^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(cc) groups attached to an N atom arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(aa))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R)₂, —OC(═O)N(R)₂, —NR^(ff)C(═O)R^(ee), —N^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR)OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR)OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR)N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee),—SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃,—C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee),—P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂,C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups attached to an N atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C_(1-6 alkyl), —OCO) ₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S;

wherein X⁻ is a counterion.

As used herein, a “counterion” is a negatively charged group associatedwith a positively charged quaternary amine in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like) and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary and quarternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(cc), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on the nitrogen atom isan amino protecting group. Amino protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),C₁₋₁₀ alkyl (e.g., aralkyl groups), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined above. Amino protecting groups are wellknown in the art and include those described in detail in ProtectingGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, ^(3rd)edition, John Wiley & Sons, 1999, incorporated herein by reference.

For example, amino protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitro cinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa))include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmo c), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloro ethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonio ethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxyb enzylcarbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexylcarbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate,p-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate,o-(N,N-dimethylcarboxamido)benzyl carbamate,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Amino protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa))include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide(Mte), 4-methoxybenzenesulfonamide (Mbs),2,4,6-trimethylbenzenesulfonamide (Mts),2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms),β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to,phenothiazinyl-(10)-carbonyl derivative, N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonyl derivative,N-benzoylphenylalanyl derivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide and 3-nitropyridinesulfenamide (Npys).

As used herein, a “leaving group” is an art-understood term referring toa molecular fragment that departs with a pair of electrons inheterolytic bond cleavage, wherein the molecular fragment is an anion orneutral molecule. See, for example, Smith, March Advanced OrganicChemistry 6th ed. (501-502).

These and other exemplary substituents are described in more detail inthe Detailed Description, the Exemplification and in the claims. Theinvention is not intended to be limited in any manner by the aboveexemplary listing of substituents.

As used herein, a “pharmaceutically acceptable form thereof” includespharmaceutically acceptable salts, hydrates, solvates, prodrugs,tautomers, isomers, and/or polymorphs of a compound of the presentinvention, as defined below and herein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

In certain embodiments, the pharmaceutically acceptable form thereof isan isomer. As used herein, the term “isomer” includes any and allgeometric isomers and stereoisomers. For example, “isomers” include cis-and trans-isomers, E- and Z-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, andother mixtures thereof, as falling within the scope of the invention.

In certain embodiments, the pharmaceutically acceptable form thereof isa tautomer. As used herein, the term “tautomer” includes two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim;enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.

In certain embodiments, the pharmaceutically acceptable form thereof isa hydrate or solvate. As used herein, the term “hydrate” refers to acompound non-covalently associated with one or more molecules of water.Likewise, “solvate” refers to a compound non-covalently associated withone or more molecules of an organic solvent.

In certain embodiments, the pharmaceutically acceptable form thereof isa prodrug. As used herein, the term “prodrug” refers to a derivative ofa parent compound that requires transformation within the body in orderto release the parent compound. In certain cases, a prodrug has improvedphysical and/or delivery properties over the parent compound. Prodrugsare typically designed to enhance pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it may enhance drug stabilityfor long-term storage.

In certain embodiments, the pharmaceutically acceptable form thereof isa polymorph. As used herein, “polymorph” refers to a compound havingmore than one crystal structure, e.g., resulting from differences inmolecular packing and/or molecular conformation of the compound in thesolid state.

SEQUENCE IDENTIFICATION NUMBERS

SEQ. ID. NO.: Homo sapiens FAAH amino acid sequence:MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENMDRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS

DETAILED DESCRIPTION I. Compounds

The present invention provides isoxazoline FAAH inhibitor compounds ofthe formula (I):

or a pharmaceutically acceptable form thereof,

wherein:

each of R^(a), R^(b), and R^(c) independently is selected from —H, C₁₋₁₀alkyl and C₁₋₁₀ perhaloalkyl, R^(d) is the group -L-Z, and Z is selectedfrom C₆₋₁₄ aryl;

L is a covalent bond or a divalent C₁ hydrocarbon group, wherein one,two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen, sulfur or nitrogen atoms;

G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion; and

each R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and 5-14membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

Group G

As defined above, G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e),—SO₂NR^(f)R^(e), —PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e),—(C═O)OR^(e), —(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NOOR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion;

and wherein R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and5-14 membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

In certain embodiments, G is not a leaving group, e.g., for example, Gis selected from —F, —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e), and—(C═O)NR^(f)R^(e).

In certain embodiments, G is selected from —CN and —NO₂. In certainembodiments, G is —CN. In certain embodiments, G is —NO₂.

In certain embodiments, G is selected from —S(═O)R^(e), —SO₂R^(e), and—SO₂NR^(f)R^(e). In certain embodiments, G is —S(═O)R^(e). In certainembodiments, G is —SO₂R^(e). In certain embodiments, G is—SO₂NR^(f)R^(e).

In certain embodiments, G is selected from —PO₂R^(e), —PO₂OR^(e) and—PO₂NR^(f)R^(e). In certain embodiments, G is —PO₂R^(e). In certainembodiments, G is —PO₂OR^(e). In certain embodiments, G is—PO₂NR^(f)R^(e).

In certain embodiments, G is selected from —(C═O)R^(e), —(C═O)OR^(e) and—(C═O)NR^(f)R^(e). In certain embodiments, G is —(C═O)R^(e). In certainembodiments, G is —(C═O)OR^(e). In certain embodiments, G is—(C═O)NR^(f)R^(e).

However, in certain embodiments, G is a leaving group, e.g., forexample, G is selected from —Cl, —Br, —I, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), and—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion.

In certain embodiments, G is a halogen; i.e., selected from —F, —Cl, —Brand —I. In certain embodiments, G is —F. In certain embodiments, G is—Br. In certain embodiments, G is —I. In certain embodiments, G is —Cl.However, in certain embodiments, G is not a halogen. For example, incertain embodiments, G is not —Br. In certain embodiments, G is not —I.In certain embodiments, G is not —F. In certain embodiments, G is not—Cl.

In certain embodiments, G is selected from —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —OSO₂R^(e), —OPO₂R^(e), —OPO₂OR^(e),—OPO₂NR^(f)R^(e), —O(C═O)R^(e), —O(C═O)OR^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is selected from—OR^(e), —O(C═O)R^(e), —O(C═O)OR^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is selected from−ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is —OR^(e). Incertain embodiments, G is —ONR^(f)R^(e). In certain embodiments, G is—ONR^(f)(C═O)R^(e). In certain embodiments, G is —ONR^(f)SO₂R^(e). Incertain embodiments, G is —ONR^(f)PO₂R^(e). In certain embodiments, G is—ONR^(f)PO₂OR^(e). In certain embodiments, G is —OSO₂R^(e). In certainembodiments, G is —OPO₂R^(e). In certain embodiments, G is —OPO₂OR^(e).In certain embodiments, G is —OPO₂NR^(f)R^(e). In certain embodiments, Gis —O(C═O)R^(e). In certain embodiments, G is —O(C═O)OR^(e). In certainembodiments, G is —O(C═O)NR^(f)R^(e). In certain embodiments, G is—O(C═NR^(f))NR^(f)R^(e).

In certain embodiments, G is selected from —OR^(e) and —SR^(e). Incertain embodiments, G is selected from —OR^(e). In certain embodiments,G is —SR^(e).

In certain embodiments, G is selected from —NR^(f)SO₂R^(e),—NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—NR^(f)(C═NR^(f))OR^(e) and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion. In certain embodiments, G is selected from —NR^(f)SO₂R^(e),—NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e) and—NR^(f)(C═O)OR^(e). In certain embodiments, G is selected from—NR^(f)SO₂R^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e) and —NR^(f)(C═O)OR^(e).In certain embodiments, G is —NR^(f)SO₂R^(e). In certain embodiments, Gis —NR^(f)PO₂R^(e). In certain embodiments, G is —NR^(f)PO₂OR^(e). Incertain embodiments, G is —NR^(f)R^(e). In certain embodiments, G is—NR^(f)(C═O)R^(e). In certain embodiments, G is —NR^(f)(C═O)OR^(e). Incertain embodiments, G is —NR^(f)(C═NR^(f))NR^(f)R^(e). In certainembodiments, G is —NR^(f)(C═NR^(f))OR^(e). In certain embodiments, G is—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion.

Additional embodiments of G, included in the description of groups R^(e)and R^(f), and further exemplified in the Tables and Examples, isprovided below and herein.

R^(e) of Group G

As defined generally above, in certain embodiments, wherein G isselected from —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e), —PO₂R^(e),—PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —OR^(e), —ONR^(f)R^(e), —ONR^(f)(C═O)R^(e),—ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e), —ONR^(f)PO₂OR^(e), —SR^(e),—OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e), —OPO₂OR^(e), —NR^(f)PO₂R^(e),—NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e), —O(C═O)R^(e), —O(C═O)OR^(e),—NR^(f)R^(e), —NR^(f)(C═O)R^(e), —NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e),—NR^(f)(C═NR^(f))NR^(f)R^(e), —O(C═NR^(f))NR^(f)R^(e),—NR^(f)(C═NR^(f))OR^(e), and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion, R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and5-14 membered heteroaryl.

In certain embodiments, R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 memberedheterocyclyl and 5-14 membered heteroaryl, wherein the alkyl, alkenyl,alkynyl, carbocycyl, aryl, heterocyclyl, and heteroaryl groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups, as defined below andherein.

In certain embodiments, R^(e) is C₁₋₁₀ alkyl. In certain embodiments,R^(e) is C₁₋₆ alkyl. In certain embodiments, R^(e) is C₁₋₅ alkylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a C₁₋₅ alkyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is a C₁₋₄ alkyl substitutedwith 0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is aC₁₋₃ alkyl substituted with 0, 1, 2 or 3 R^(h) groups. In certainembodiments, R^(e) is a C₁₋₂ alkyl substituted with 0, 1 or 2 R^(h)groups. Exemplary alkyl groups include, but are not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tent-butyl,pentyl, isopentyl, neopentyl, and hexyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is a C₁₋₆ perhaloalkyl. In certainembodiments, R^(e) is a C₁₋₅ perhaloalkyl. In certain embodiments, R^(e)is a C₁₋₂ perhaloalkyl. In certain embodiments, R^(e) is a C₁₋₃perhaloalkyl. In certain embodiments, R^(e) is a C₁₋₂ perhaloalkyl.Exemplary R^(e) perhaloalkyl groups include, but are not limited to,—CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, and —CF₂Cl.

In certain embodiments, R^(e) is C₂₋₁₀ alkenyl. In certain embodiments,R^(e) is C₂₋₆ alkenyl. In certain embodiments, R^(e) is a C₂₋₆ alkenylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a C₂₋₅ alkenyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is a C₂₋₃ alkenylsubstituted with 0, 1, 2, or 3 R^(h) groups. Exemplary alkenyl groupsinclude, but are not limited to, ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl and hexenyl,wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups.

In certain embodiments, R^(e) is C₂₋₁₀ alkynyl. In certain embodiments,R^(e) is C₂₋₆ alkynyl. In certain embodiments, R^(e) is C₂₋₆ alkynylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is C₂₋₅ alkynyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is C₂₋₄ alkynyl substitutedwith 0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is C₂₋₃alkynyl substituted with 0, 1, 2 or 3 R^(h) groups. Exemplary R^(e)alkynyl groups include, but are not limited to, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, pentynyl and hexynyl, wherein suchgroups are substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

However, in certain embodiments, wherein G is —OR^(e), then R^(e) is notC₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, aralkyl). In certainembodiments, wherein G is —OR^(e), then R^(e) is not C₂₋₆ alkenyl (e.g.,allyl).

In certain embodiments, wherein G is —SR^(e), then R^(e) is not thenR^(e) is not C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,aralkyl).

In certain embodiments, wherein G is —NR^(e)R^(f) and R^(f) is —H orC₁₋₃ alkyl (e.g., methyl, ethyl, aralkyl) then R^(e) is not C₁₋₆ alkyl.

In certain embodiments, R^(e) is C₆₋₁₄ aryl. In certain embodiments,R^(e) is C₆₋₁₀ aryl. In certain embodiments, R^(e) is C₆₋₁₀ arylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is C₆ aryl (e.g., phenyl) substituted with 0, 1, 2,3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a C₁₀ aryl(e.g., naphthyl) substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is phenyl. In certain embodiments, R^(e)is phenyl substituted with 0, 1, 2, 3 or 4 R^(h) groups. In certainembodiments, R^(e) is phenyl substituted with 0, 1, 2 or 3 R^(h) groups.In certain embodiments, R^(e) is phenyl substituted with 0, 1 or 2 R^(h)groups. In certain embodiments, R^(e) is phenyl substituted with 0 or 1R^(h) groups. In certain embodiments, R^(e) is a disubstituted phenyl(i.e., substituted with 2 R^(h) groups). In certain embodiments, R^(e)is a monosubstituted phenyl (i.e., substituted with 1 R^(h) group). Incertain embodiments, R^(e) is an unsubstituted phenyl (i.e., substitutedwith 0 R^(h) groups).

In certain embodiments, R^(e) is phenyl substituted with at least oneortho R^(h) group. In certain embodiments, R^(e) is phenyl substitutedwith at least one meta R^(h) group. In certain embodiments, R^(e) isphenyl substituted with at least one para R^(h) group.

In certain embodiments, R^(e) is a phenyl group of the formula:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1. In certain embodiments, x is 3. Incertain embodiments, R^(e) is a disubstituted phenyl group (i.e.,wherein x is 2). In certain embodiments, R^(e) is a monosubstitutedphenyl group (i.e., wherein x is 1). In certain embodiments, R^(e) is anunsubstituted phenyl group (i.e., wherein x is 0).

For example, in certain embodiments, R^(e) is a substituted orunsubstituted phenyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a naphthyl. In certain embodiments,R^(e) is a naphthyl group of any one of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1. In certain embodiments, R^(e) is atrisubstituted naphthyl group (i.e., wherein x is 3). In certainembodiments, R^(e) is a disubstituted naphthyl group (i.e., wherein x is2). In certain embodiments, R^(e) is a monosubstituted naphthyl group(i.e., wherein x is 1). In certain embodiments, R^(e) is anunsubstituted naphthyl group (i.e., wherein x is 0).

For example, in certain embodiments, R^(e) is a substituted orunsubstituted 1-naphthyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted2-naphthyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

However, in certain embodiments, wherein G is —OR^(e), then R^(e) is notC₁₀ aryl (e.g., 1-naphthyl, 2-naphthyl).

In certain embodiments, R^(e) is 5-14 membered heteroaryl. In certainembodiments, R^(e) is a 5-10 membered heteroaryl substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a 5-8membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. Incertain embodiments, R^(e) is a 5-6 membered heteroaryl substituted with0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is a 9-10membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

Exemplary R^(e) heteroaryl groups include, but are not limited to,pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl,4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl,indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl,dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl andphenazinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5R^(h) groups.

In certain embodiments, R^(e) is a 5-membered heteroaryl. In certainembodiments, R^(e) is a 5-membered heteroaryl substituted with 0, 1, 2or 3 R^(h) groups. In certain embodiments, R^(e) is a 5-memberedheteroaryl selected pyrrolyl, furanyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl, wherein such groups aresubstituted with 0, 1, 2 or 3 R^(h) groups.

For example, in certain embodiments, R^(e) is a 5-membered heteroaryl ofthe formula:

wherein Y^(a), Y^(b), Y^(c) and Y^(d) are, independently, selected fromCH, CR^(h), O, S, N, or NR^(k), with the proviso that at least one ofY^(a), Y^(b), Y^(c) and Y^(d) is O, S, N or NR^(k), and wherein R^(h)and R^(k) are defined below and herein.

In certain embodiments of the above formula (i-d), Y^(a) is O, S, N, orNR^(k) and Y^(b), Y^(c) and Y^(d) are, independently, selected from CH,CR^(h), NR^(k) or N. In certain embodiments of the above formula (i-d),Y^(a) is O, S, N, or NR^(k) and Y^(b), Y^(c) and Y^(d) are,independently, selected from CH or CR^(h). In certain embodiments of theabove formula (i-d), Y^(a) is O, S, or NR^(k), Y^(c) is N and Y^(b) andY^(d) are, independently, selected from CH or CR^(h).

In certain embodiments of the above formula (i-d), Y^(b) is O, S, orNR^(k) and Y^(a), Y^(c) and Y^(d) are, independently, selected from CH,CR^(h) or N. In certain embodiments of the above formula (i-d), Y^(b) isO, S, or NR^(k) and Y^(a), Y^(c) and Y^(d) are, independently, selectedfrom CH or CR^(h). In certain embodiments of the above formula (i-d),Y^(b) is O, S, or or NR^(k), Y^(d) is N and Y^(a) and Y^(c) are,independently, selected from CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted5-membered heteroaryl of any one of the formulae:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein. In certain embodiments, R^(e) is an unsubstituted 5-memberedheteroaryl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted 5-membered heteroaryl (e.g., wherein x is 1 or 2). Incertain embodiments, R^(e) is a monosubstituted 5-membered heteroaryl(i.e., wherein x is 1). In certain embodiments, R^(e) is a disubstituted5-membered heteroaryl (i.e., wherein x is 2). In certain embodiments, xis 0, 1 or 2. In certain embodiments, x is 0 or 1.

However, in certain embodiments, wherein G is —OR^(e), R^(e) is notthiazolyl, e.g., of the formula:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein.

In certain embodiments, R^(e) is a 6-membered heteroaryl. In certainembodiments, R^(e) is a 6-membered heteroaryl substituted with 0, 1, 2,3 or 4 R^(h) groups. In certain embodiments, R^(e) is a 6-memberedheteroaryl selected from the group consisting of pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl,wherein such groups are substituted with 0, 1, 2, 3 or 4 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6-membered heteroarylgroup of the formula:

wherein W^(a), W^(b), W^(c), W^(d) and W^(e) are, independently,selected from CH, CR^(h) or N, with the proviso that at least one ofW^(a), W^(b), W^(c), W^(d) and W^(e) is N, and wherein R^(h) is asdefined below and herein.

In certain embodiments, R^(e) is a pyrindinyl group. In certainembodiments, R^(e) is a pyrindinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups. For example, in certain embodiments, R^(e) is apyrindinyl group of the formula:

wherein x is 0, 1, 2, 3 or 4, and R^(h) is as defined below and herein.In certain embodiments, R^(e) is an unsubstituted pyrindinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyrindinyl (e.g., wherein x is 1, 2, 3 or 4). In certain embodiments,R^(e) is a monosubstituted pyrindinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted pyrindinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted pyrindinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a 2-pyrindinyl group, e.g., of theformula (i-e) wherein W^(a) is N and W^(b), W^(c), W^(d) and W^(e) are,independently, CH or CR^(h). In certain embodiments R^(e) is a3-pyrindinyl group, e.g., of the formula (i-e) wherein W^(b) is N andW^(a), W^(c), W^(d) and W^(e) are, independently, CH or CR^(h). Incertain embodiments R^(e) is a 4-pyrindinyl group, e.g., of the formula(i-e) wherein W^(c) is N and W^(a), W^(b), W^(d) and W^(e) are,independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted2-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted3-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyridazinyl group. In certainembodiments, R^(e) is a pyridazinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is apyridazinyl group of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyridazinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyridazinyl (e.g., wherein x is 1, 2 or 3). In certain embodiments,R^(e) is a monosubstituted pyridazinyl (i.e., wherein x is 1). Incertain embodiments, R^(e) is a disubstituted pyridazinyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted pyridazinyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a 3-pyridazinyl group, e.g., of theformula (i-e) wherein W^(a) and W^(b) are N and W^(c), W^(d) and W^(e)are, independently, CH or CR^(h). In certain embodiments R^(e) is a4-pyridazinyl group, e.g., of the formula (i-e) wherein W^(b) and W^(c)are N and W^(a), W^(d) and W^(e) are, independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted3-pyridazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyridazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyrimidinyl group. In certainembodiments, R^(e) is a pyrimidinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is apyrimidinyl group of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrimidinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyrimidinyl (e.g., wherein x is 1, 2 or 3). In certain embodiments,R^(e) is a monosubstituted pyrimidinyl (i.e., wherein x is 1). Incertain embodiments, R^(e) is a disubstituted pyridazinyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted pyrimidinyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a 2-pyrimidinyl group, e.g., of theformula (i-e) wherein W^(a) and W^(e) are N and W^(b), W^(c) and W^(d)are, independently, CH or CR^(h). In certain embodiments R^(e) is a4-pyrimidinyl group, e.g., of the formula (i-e) wherein W^(a) and W^(c)are N and W^(b), W^(d) and W^(e) are, independently, CH or CR^(h). Incertain embodiments R^(e) is a 5-pyrimidinyl group, e.g., of the formula(i-e) wherein W^(b) and W^(d) are N and W^(a), W^(c) and W^(e) are,independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted2-pyrimidinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyrimidinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted5-pyrimidinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyrazinyl group. In certainembodiments, R^(e) is a pyrazinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is a pyrazinylgroup of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1, 2 or 3). In certain embodiments, R^(e) is amonosubstituted pyrazinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted pyrazinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted pyrazinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedpyrazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments R^(e) is a triazinyl group. In certainembodiments R^(e) is a triazinyl group substituted with 0, 1 or 2 R^(h)groups. For example, in certain embodiments, R^(e) is a triazinyl groupof the formula:

wherein x is 0, 1 or 2, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1 or 2). In certain embodiments, R^(e) is a monosubstitutedpyrazinyl (i.e., wherein x is 1). In certain embodiments, R^(e) is adisubstituted pyrazinyl (i.e., wherein x is 2). In certain embodiments,x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedtriazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments R^(e) is a tetrazinyl group. In certainembodiments R^(e) is a tetrazinyl group substituted with 0 or 1 R^(h)groups. For example, in certain embodiments, R^(e) is a tetrazinyl groupof the formula:

wherein x is 0 or 1, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1). In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedtetrazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a 9-membered heteroaryl (e.g., a5,6-bicyclic heteroaryl). In certain embodiments, R^(e) is a5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 5,6-bicyclic heteroarylselected from indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5R^(h) groups.

For example, in certain embodiments, R^(e) is a 5,6-bicyclic heteroarylof the formula:

wherein Y^(e), Y^(f), Y^(g), Y^(i), Y^(j), Y^(k) and Y^(m) are,independently, C, CH, CR^(h), O, S, N, or NR^(k) and V is C or N, withthe proviso that at least one of Y^(e), Y^(f), Y^(g) is selected from O,S, N or NR^(k) wherein R^(h) and R^(k) are as defined below and herein.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl group of theformula (i-f), wherein Y^(e) is selected from O, S, or NR^(k), Y^(n) isC, and Y^(f), Y^(g), Y^(i), Y^(j), Y^(k) and Y^(m) are, independently,C, CH, or CR^(h). For example, in certain embodiments, R^(e) is a5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is selected from O, S, or NR^(k); Y^(g) is N; V is C; Y^(f) is C, CH, orCR^(h) or N, and Y^(i), Y^(j), Y^(k) and Y^(m) are, independently, C,CH, or CR^(h). For example, in certain embodiments, R^(e) is a5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is NR^(k), S or O; Y^(m) is N; Y^(n) is C; and Y^(f), Y^(g), Y^(i),Y^(j), and Y^(k) are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is a 5,6-bicyclic heteroaryl group of theformulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein yg isO, S, or NR^(k); Y^(m) is N; V is C; and Y^(e), Y^(f), Y^(i), Y^(j) andY^(k) are, independently, C, CH, or CR^(h). For example, in certainembodiments, R^(e) is a 5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is selected from N; V is N; and Y^(f), Y^(i), Y^(j), Y^(k) and Y^(m)are, independently, C, CH, or CR^(h). For example, in certainembodiments, R^(e) is a 5,6-bicyclic heteroaryl group of the formula:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 10-membered heteroaryl (e.g., a6,6-bicyclic heteroaryl). In certain embodiments, R^(e) is a6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 6,6-bicyclic heteroarylselected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, wherein suchgroups are substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6,6-bicyclic heteroarylof the formula:

wherein W^(f), W^(g), W^(h), W^(i), W^(j), W^(k), W^(m) and W^(n) are,independently, selected from C, CH, CR^(h) or N, with the proviso thatat least one of W^(f), W^(g), W^(h), W^(i), W^(j), W^(k), W^(m) andW^(n) is N, and wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a quinolinyl group; e.g., of theformula (i-g) wherein W^(i) is N and W^(g), W^(h), W^(f), W^(j), W^(k),W^(m) and W^(n) are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is a quinolinyl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted quinolinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedquinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain embodiments,R^(e) is a monosubstituted quinolinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted quinolinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted quinolinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is an isoquinolinyl group; e.g., of theformula (i-g) wherein W^(h) is N and W^(f), W^(g), W^(i), W^(j), W^(k),W^(m) and W^(n) are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is an isoquinolinyl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted isoquinolinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedisoquinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted isoquinolinyl (i.e., wherein xis 1). In certain embodiments, R^(e) is a disubstituted isoquinolinyl(i.e., wherein x is 2). In certain embodiments, R^(e) is atrisubstituted isoquinolinyl (i.e., wherein x is 3). In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a quinoxalinyl group; e.g., of theformula (i-g) wherein W^(f) and W^(i) are N and W^(g), W^(h), W^(j),W^(k), W^(m) and W^(n) are, independently, C, CH, or CR^(h). Forexample, in certain embodiments, R^(e) is a quinoxalinyl group of theformulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted quinoxalinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedquinoxalinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted quinoxalinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted quinoxalinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedquinoxalinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1,2 or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments,x is 0 or 1.

In certain embodiments, R^(e) is a 3-14 membered heterocyclyl. Incertain embodiments, R^(e) is a 3-14 membered heterocyclyl substitutedwith 0, 1, 2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a5-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 5-8 membered heterocyclylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a 5-6 membered heterocyclyl substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a 9-10membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

Exemplary heterocyclyl R^(e) groups include, but are not limited to,azirdinyl, oxiranyl, thiorenyl, az etidinyl, oxetanyl, thietanyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione,dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl,thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl,thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl,azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl,isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl,chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl,1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrro lyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, and 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is a 6-membered heterocyclyl substitutedwith 0, 1, 2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl,dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl,dioxanyl, and triazinanyl, wherein such groups are substituted with 0,1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6-membered heterocyclylof the formula:

wherein W^(o), W^(p), W^(q), W^(r), and W^(s) are, independently,selected from CH₂, CHR^(h), C(R^(h))₂, NR^(k), O or S, and W^(t) is N,CH, CR^(h), with the proviso that at least one of W^(o), W^(p), W^(q),W^(r) and W^(s) is selected from N, NR^(k), O or S, and wherein R^(h)and R^(k) are defined below and herein.

In certain embodiments, R^(e) is a piperidinyl group. In certainembodiments, R^(e) is a piperidinyl group substituted with 0, 1, 2, 3, 4or 5 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedpiperidinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted piperidinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted piperidinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted piperidinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedpiperidinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 1-piperidinyl group, e.g., of theformula (i-h) wherein W^(t) is N and W^(o), W^(p), W^(q), W^(r), andW^(s) are, independently, selected from CH₂, CHR^(h), C(R^(h))₂. Incertain embodiments, R^(e) is a 2-piperidinyl group, e.g., of theformula (i-h) wherein W^(o) is NR^(k); W^(p), W^(q), W^(r), and W^(s)are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h). In certain embodiments, R^(e) is a 3-piperidinyl group, e.g., ofthe formula (i-h) wherein W^(p) is NR^(k); W^(o), W^(q) W^(r), and W^(s)are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h). In certain embodiments, R^(e) is a 4-piperidinyl group, e.g., ofthe formula (i-h) wherein W^(q) is NR^(k); W^(o), W^(p), W^(r), andW^(s) are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h).

In certain embodiments, R^(e) is a piperazinyl group. In certainembodiments, R^(e) is a piperazinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedpiperazinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted piperazinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted piperazinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted piperazinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedpiperazinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 1-piperazinyl group, e.g., of theformula (i-h) wherein W^(t) is N, W^(q) is NR^(k) and W^(o), W^(p),W^(r), and W^(s) are, independently, selected from CH₂, CHR^(h),C(R^(h))₂. In certain embodiments, R^(e) is a 2-piperazinyl group, e.g.,of the formula (i-h) wherein W^(o) and W^(r) are independently NR^(k)and W^(p), W^(q), W^(r), and W^(s) are, independently, CHR^(h),C(R^(h))₂, or CH₂; and W^(t) is CH or CR^(h).

In certain embodiments, R^(e) is a morpholinyl group. In certainembodiments, R^(e) is a morpholinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedmorpholinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted morpholinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted morpholinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted morpholinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedmorpholinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a morpholinyl group of the formula(i-h) wherein W^(t) is N, W^(q) is O and W^(o), W^(p), W^(r), and W^(s)are, independently, selected from CH₂, CHR^(h), C(R^(h))₂.

In certain embodiments, R^(e) is a dioxanyl group. In certainembodiments, R^(e) is a dioxanyl group substituted with 0, 1, 2, 3 or 4R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstituteddioxanyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted dioxanyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted dioxanyl (i.e., wherein x is 1).In certain embodiments, R^(e) is a disubstituted dioxanyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted dioxanyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a dioxanyl group, e.g., of the formula(i-h) wherein W^(o) and W^(r) are O and W^(p), W^(q), W^(r), and W^(s)are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h).

Other 6-membered heterocycyl R^(e) groups encompassed by formula (i-h)include monosaccharide sugars, e.g., for example, pyranosides selectedfrom ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, iodose, galactose and talose.

In certain embodiments, R^(e) is a C₃₋₁₀ carbocycyl. In certainembodiments, R^(e) is a C3-10 carbocycyl substituted with 0, 1, 2, 3, 4,or 5 R^(h) groups. In certain embodiments, R^(e) is a C5-8 carbocycylsubstituted with 0, 1, 2, 3, 4, or 5 R^(h) groups. In certainembodiments, R^(e) is a C5-6 carbocycyl substituted with 0, 1, 2, 3 or 4R^(h) groups. In certain embodiments, R^(e) is a C9-10 carbocycylsubstituted with 0, 1, 2, 3, 4, or 5 R^(h) groups.

Exemplary R^(e) C₃₋₁₀ carbocycyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cyclohexadienyl, cycloheptyl, and cycloheptadienyl,wherein such groups are substituted with 0, 1, 2, 3, 4, or 5 R^(h)groups.

R^(f) of Group G

As defined generally above, in certain embodiments, wherein G isselected from —SO₂NR^(f)R^(e), —PO₂NR^(f)R^(e), —(C═O)NR^(f)R^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —NR^(f)SO₂R^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e),—OPO₂NR^(f)R^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e), —NR^(f)(C═O)OR^(e),—O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NOOR^(e), and—[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion, each R^(f) attached to a nitrogen atom is,independently, selected from —H or C₁₋₁₀ alkyl, or an amino protectinggroup, or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

In certain embodiments, R^(f) is H or a C₁₋₁₀ alkyl group.

In certain embodiments, R^(f) is H.

In certain embodiments, R^(f) is a C₁₋₁₀ alkyl group. In certainembodiments, R^(f) is C₁₋₁₀ alkyl substituted with 0, 1, 2, 3, 4, or 5R^(h) groups. Exemplary R^(f) alkyl groups include, but are not limitedto, methyl, ethyl, propyl, allyl, and benzyl. In certain embodiments,R^(f) an unsubstituted methyl, i.e., —CH₃. In certain embodiments, R^(f)an unsubstituted ethyl, i.e., —CH₂CH₃.

In certain embodiments, R^(f) is an amino protecting group. For example,in certain embodiments, R^(f) is selected from —OH, —OR^(i), —N(R^(k))₂,—C(═O)R^(i), —C(═O)N(R^(k))₂, —CO₂R^(i), —SO₂R^(i), —C(═NR^(k))R^(i),—C(═NR^(k))OR^(j), —C(═NR^(k))N(R^(k))₂, —SO₂N(R^(k))₂, —SO₂R^(i),—SO₂OR^(i), —SOR^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(m) groups, wherein R^(i), R^(k), R^(m) are as definedbelow and herein.

However, in certain embodiments, G is —NR^(e)R^(f) and R^(f) is —H orC₁₋₃ alkyl, then R^(e) is not C₁₋₆ alkyl or thiazolyl.

Moreover, in certain embodiments, wherein G is —OC(═O)NR^(f)R^(e), thenR^(e) and R^(f) are not both —CH₃.

Alternatively, in certain embodiments, R^(e) and R^(f) are joined toform an 3-14 membered heterocyclyl ring or an 5-14 membered heteroarylring; e.g., for example, when G is —SO₂NR^(f)R^(e), —PO₂NR^(f)R^(e),—(C═O)NR^(f)R^(e), —ONR^(f)R^(e), —OPO₂NR^(f)R^(e), —NR^(f)R^(e),—O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion. In certain embodiments, wherein R^(e) and R^(f) are joinedto form an 3-14 membered heterocyclyl ring or an 5-14 memberedheteroaryl ring, the heterocyclyl ring or heteroaryl ring aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups, as defined below andherein.

In certain embodiments, R^(e) and R^(f) are joined to form an 3-14membered heterocyclyl ring. In certain embodiments, R^(e) and R^(f) arejoined to form a 3-14 membered heterocyclyl ring substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, and R^(f) are joinedto form a 5-10 membered heterocyclyl ring substituted with 0, 1, 2, 3,4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joinedto form a 5-8 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4,or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined toform a 5-6 membered heterocyclyl ring substituted with 0, 1, 2 or 3R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined to forma 9-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5R^(h) groups.

In certain embodiments, R^(e) and R^(f) are joined to form aheterocyclyl group selected from azirdinyl, azetidinyl, pyrrolidinyl,dihydropyrrolyl, pyrrolyl-2,5-dione, triazolinyl, oxadiazolinyl,thiadiazolinyl, piperidinyl, dihydropyridinyl, thianyl, piperazinyl,morpholinyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl,indolinyl, isoindolinyl, tetrahydrobenzo-thienyl, tetrahydroindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,decahydroisoquinolinyl, indolinyl, and phthalimidyl, wherein such groupsare substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) and R^(f) are joined to forma 5-membered heterocyclyl ring selected from the group:

wherein x is 0, 1, 2 or 3, wherein R^(h) and R^(k) are as defined belowand herein.

In certain embodiments, R^(e) and R^(f) are joined to form a 6-memberedheterocyclyl ring selected from the group:

wherein x is 0, 1, 2 or 3, wherein R^(h) and R^(k) are as defined belowand herein.

However, in certain embodiments, wherein G is —NR^(e)R^(f), then R^(e)and R^(f) are not joined to form a pyrrolidinyl, piperidinyl or azepanylring.

In certain embodiments, R^(e) and R^(f) are joined to form a 5-14membered heteroaryl ring. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-14 membered heteroaryl ring substituted with 0, 1, 2,3, 4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-10 membered heteroaryl ring substituted with 0, 1, 2,3, 4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-8 membered heteroaryl ring substituted with 0, 1, 2,3 or 4 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joinedto form a 5-6 membered heteroaryl ring substituted with 0, 1, 2, 3 or 4R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined to forma 9-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5R^(h) groups.

In certain embodiments, R^(e) and R^(f) are joined to form a 5-memberedheteroaryl ring selected from:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein.

However, in certain embodiments, wherein G is —NR^(f)R^(e), R^(e) andR^(f) are not joined to form a 1,2,4-triazolyl ring, e.g. of theformula:

wherein x is 0 or 1, and R^(h) is as defined below and herein.

In certain embodiments, R^(e) and R^(f) are joined to form a 9-memberedheteroaryl (“5,6-bicyclic heteroaryl”) ring selected from:

wherein x is 0, 1, 2 or 3 and R^(h) and R^(k) are as defined below andherein.

Group G Substituents Embodiments of R^(h)

As used above and herein each instance of R^(h) is, independently,selected from halogen (fluoro (—F), bromo (—Br), chloro (—Cl), and iodo(—I)), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(i), —ON(R^(k))₂,—N(R^(k))₂, —N(R^(k))₃ ⁺X⁻, —N(OR)R^(k), —SH, —SR^(i), —SSRj,—C(═O)R^(i), —CO₂H, —CHO, —CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i),—C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═NR^(k))R^(i), —C(═NR^(k))OR^(i),—OC(═NR^(k))R^(i), —OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂,—OC(═NR^(k))N(R^(k))₂, —NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(k)SO₂R^(i), —SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i),—S(═O)R^(i), —OS(═O)R^(i), —Si(R^(i))₃, —OS^(i)(R^(i))₃—C(═S)N(R^(k))₂,—C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i), —P(═O)₂R^(i), —OP(═O)₂R^(i),—P(═O)(R^(i))₂, —OP(═O)(R^(i))₂, —OP(═O)(OR)₂, —P(═O)₂N(R^(k))₂,—OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂, —OP(═O)(NR^(k))₂,—NR^(k)P(═O)(OR^(j))₂, —NR^(k)P(═O)(NR^(k))₂, —P(R)₂, —P(R)₃, —OP(R)₂,—OP(R)₃, —B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₄ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups;

each instance of R^(i) is, independently, selected from C₁₋₁₀alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups;

each instance of R^(k) is, independently, selected from hydrogen, —OH,—OR^(i), —N(R)₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂, —CO₂R^(i),—SO₂R^(i), —C(═NR^(j))OR^(i), —C(═NR^(j))N(R^(j))₂, —SO₂N(R^(j))₂,—SO₂R^(j), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂, —C(═O)SR^(j),—C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂, —P(═O)₂N(R^(j))₂,—P(═O)(NR^(j))₂, C₁₋₁₀ alkyl, C₂₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(j) groups attached to an N atom arejoined to foR^(m) a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(m) groups; each instance of R^(j) is, independently,selected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl,and 5-14 membered heteroaryl, or two R^(j) groups attached to an N atomare joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(m) groups; each instance of R^(m) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂,—N(R^(n))₃ ⁺X⁻, —N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o),—CO₂H, —CO₂R^(o), —OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂,—OC(═O)N(R^(n))₂, —NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o),—NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o),—OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂,—NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o),—SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o), —Si(R^(o))₃, —OSi(R^(o))₃,—C(═S)N(R^(n))₂, —C(═O)SR^(o), —C(═S)SR^(o), —SC(═S)SR^(o),—P(═O)₂R^(o), —P(═O)(R^(o))₂, —OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂,C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups, or two geminal R^(m) substituents can bejoined to form ═O or ═S;

each instance of R^(o) is, independently, selected from C₁₋₆alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups;

each instance of R^(n) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆-perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(n) groups attached to an N atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; and

each instance of R^(p) is, independently, fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),—N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl),—OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),—NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₁₆ alkyl, —SO₂OC₁₋₁₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₄ aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; or twogeminal R^(p) substituents can be joined to form ═O or ═S;

wherein X⁻ is a counterion.

In certain embodiments, R^(h) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i), —SO₂H,—SO₃H, —N(R^(k))₂, —N(R^(k))₃ ⁺X⁻, —C(═O)R^(i), —CO₂H, —CHO, —CO₂R^(i),—OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂,—NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂,—C(═NR^(k))R^(i), —C(═NR^(k))OR^(i), —OC(═NR^(k))R^(i),—OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —OC(═NR^(k))N(R^(k))₂,—NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i), —S(═O)R^(i),—OS(═O)R^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i),—P(═O)₂R^(i), —OP(═O)₂R^(i), —P(═O)(R^(i))₂, —OP(═O)(R^(i))₂,—OP(═O)(OR^(j))₂, —P(═O)₂N(R^(k))₂, —OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂,—OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR)₂, —NR^(k)P(═O)(NR^(k))₂, —B(OR)₂,—BR^(i)(OR^(j)), C₁₋₁₀ alkyl, —C₁₋₁₀ perhaloalkyl, C₃₋₁₄ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; andwherein X⁻ is a counterion.

In certain embodiments, R^(h) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i),—N(R^(k))₂, —N(R^(k))₃ ⁺X⁻, —C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i),—OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i),—NR^(k)CO₂R^(i), NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(k)SO₂R^(i), —SO₂N(R^(k))₂, —SO₂R^(i), C₁₋₁₀ alkyl, C₆ aryl, and 5-6membered heteroaryl, wherein each alkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3 or 4 R^(m) groups; and whereinX⁻ is a counterion.

In certain embodiments, R^(h) is —OR^(i), e.g., selected from —OCH₃,—OCF₃, —OCH₂CH₃, —OCH₂CF₃, -OiPr and -OnBu.

In certain embodiments, R^(h) is —SR^(i), e.g., selected from —SCH₃.

In certain embodiments, R^(h) is —N(R^(k))₂ or —N(R^(k))₃ ⁺X⁻, e.g.,selected from —NH₂ and —NH₃ ⁺X⁻.

In certain embodiments, R^(h) is —C(═O)R^(i), e.g., selected from—C(═O)CH₃.

In certain embodiments, R^(h) is —CO₂R^(i), e.g., selected from —CO₂CH₃.

In certain embodiments, R^(h) is —C(═O)N(R^(k))₂, e.g., selected from—C(═O)NHOH, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,—C(═O)NHCH₂CF₃ —C(═O)NH(CH₂)₁₋₆NH₃ ⁺X⁻, —C(═O)NHCH₂C(═O)OCH₃,—C(═O)NHCH₂C(═O)OH and —C(═O)NHCH₂CH₂OH.

In certain embodiments, R^(h) is —OC(═O)R^(i), e.g., selected from—OC(═O)CH₃.

In certain embodiments, R^(h) is —OCO₂R^(i), e.g., selected from—OCO₂CH₃.

In certain embodiments, R^(h) is —OC(═O)N(R^(k))₂, e.g., selected from—OC(═O)NH₂.

In certain embodiments, R^(h) is —NR^(k)C(═O)R^(i), e.g., selected from—NHC(═O)CH₃.

In certain embodiments, R^(h) is —NR^(k)CO₂R^(i), e.g., selected from—NHC(═O)OCH₃ and —NHC(═O)OtBu.

In certain embodiments, R^(h) is —NR^(k)C(═O)N(R^(k))₂, e.g., selectedfrom —NHC(═O)NH₂.

In certain embodiments, R^(h) is —C(═O)NR^(k)SO₂R^(i), e.g., selectedfrom —C(═O)NHSO₂CH₃, —C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉ and—C(═O)NHSO₂iBu.

In certain embodiments, R^(h) is —NR^(k)SO₂R^(i), e.g., selected from—NHSO₂CH₃.

In certain embodiments, R^(h) is —SO₂N(R^(k))₂, e.g., selected from—SO₂NH₂, —SO₂N(CH₃)₂.

In certain embodiments, R^(h) is —SO₂R^(i), e.g., selected from —SO₂CH₃,—SO₂CH₂CH₃, —SO₂C₅H₉ and —SO₂iBu.

In certain embodiments, R^(h) is C₁₋₁₀ alkyl, e.g., selected from —CH₃,—CH₂CH₃, -iPr, -nBu, —CF₃, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂H and —CH₂CH₂CO₂NH₂.

In certain embodiments, R^(h) is selected from —C(═O)R^(i), —CO₂H, and—SO₂R^(i). In certain embodiments, R^(h) is —C(═O)R^(i). In certainembodiments, R^(h) is —SO₂R^(i). In certain embodiments, R^(h) is —CO₂Hor —SO₂CH₃. In certain embodiments, R^(h) is —CO₂H. In certainembodiments, R^(h) is —SO₂CH₃.

In certain embodiments, each instance of R^(h) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), iodo (—I), —NH₂,—NH₃ ⁺X⁻, —CN, —NO₂, —SO₂CH₃, —SO₂CH₂CH₃, —SO₂C₅H₉, —SO₂iBu, —SO₂NH₂,—SO₂N(CH₃)₂, —C(═O)NHSO₂CH₃, —C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉,—C(═O)NHSO₂iBu, —C(═O)CH₃, —CO₂H, —CO₂CH₃, —OC(═O)CH₃, —OCO₂CH₃,—C(═O)NHOH, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,—C(═O)NHCH₂CF₃—C(═O)NH(CH₂)₁₋₆NH₃ ⁺X⁻, —OC(O)NH₂, —NHC(═O)CH₃,—NHC(═O)OCH₃, —NHC(═O)OtBu, —NHC(═O)NH₂, —NHSO₂CH₃, —CH₃, —CH₂CH₃, -iPr,-nBu, —CF₃, —OH, —OCH₃, —SCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CF₃, -OiPr, -OnBu,—CH₂CH₂CO₂Me, —CH₂CH₂CO₂H, —CH₂CH₂CO₂NH₂, C(═O)NHCH₂C(═O)OCH₃,—C(═O)NHCH₂C(═O)OH, —C(═O)NHCH₂CH₂OH, C₆ aryl substituted with 0, 1, or2 R^(m) groups and 5-6 membered heteroaryl substituted with 0, 1, or 2R^(m) groups; and wherein X⁻ is a counterion.

In certain embodiments, R^(h) is a C₆ aryl (e.g., phenyl)substitutedwith 0, 1, or 2 R^(m) groups. In certain embodiments, R^(h) is a C₆ aryl(e.g., phenyl) substituted with 1 R^(m) group, and R^(m) is —CO₂H,—CO₂CH₃, —CO₂CH₂CH₃, and —C(═O)NH₂.

In certain embodiments, R^(h) is a 5-6 membered heteroaryl substitutedwith 0, 1, or 2 R^(m) groups. In certain embodiments, R^(h) is a 5membered heteroaryl substituted with 0, 1, or 2 R^(m) groups. Exemplary5 membered heteroaryl R^(h) groups include, but are not limited to,pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl, wherein such groups are substituted with 0or 1 R^(m) groups. In certain embodiments, the R^(h) 5 memberedheteroaryl group is selected from pyrazolyl and oxadiazolyl, whereinsuch groups are substituted with 0 or 1 R^(m) groups.

Embodiments of R^(i)

In certain embodiments, each instance of R^(i) is, independently,selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is unsubstituted.

In certain embodiments, R^(i) is unsubstituted C₁₋₁₀ alkyl. In certainembodiments, R^(i) is C₁₋₁₀ perhaloalkyl. In certain embodiments, R^(i)is unsubstituted C₂₋₁₀ alkenyl. In certain embodiments, R^(i) isunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, R^(i) isunsubstituted C₃₋₁₀ carbocyclyl. In certain embodiments, R^(i) isunsubstituted 3-14 membered heterocyclyl. In certain embodiments, R^(i)is unsubstituted C₆₋₁₄ aryl. In certain embodiments, R^(i) isunsubstituted 5-14 membered heteroaryl.

Embodiments of R^(m)

In certain embodiments, each instance of R^(m) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂,—N(R^(n))₃ ⁺X⁻, —N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o),—CO₂H, —CO₂R^(o), —OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂,—OC(═O)N(R^(n))₂, —NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o),—NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o),—OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂,—NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o),—SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o), —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups.

In certain embodiments, each instance of R^(m) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂,—N(R^(n))₃ ⁺X⁻, —N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o),—CO₂H, —CO₂R^(o), —OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂,—OC(═O)N(R^(n))₂, —NRnC(═O)R^(o), —NR^(n)CO₂R^(o),—NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o),—OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂,—NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o),—SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o), —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14 memberedheteroaryl.

In certain embodiments, R^(m) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —NH₂, —NH₃ ⁺X⁻, —CN, —NO₂, —SO₂CH₃,—SO₂CH₂CH₃, —SO₂C₅H₉, —SO₂iBu, —SO₂NH₂, —SO₂N(CH₃)₂, —C(═O)NHSO₂CH₃,—C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉, —C(═O)NHSO₂iBu, —C(═O)CH₃, —CO₂H,—CO₂CH₃, —OC(═O)CH₃, —OCO₂CH₃, —C(═O)NHOH, —C(═O)NH₂, —C(═O)NHCH₃,—C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃, —C(═O)NHCH₂CF₃ —C(═O)NH(CH₂)₁₋₆NH₃ ⁺X⁻,—OC(O)NH₂, —NHC(═O)CH₃, —NHC(═O)OCH₃, —NHC(═O)OtBu, —NHC(═O)NH₂,—NHSO₂CH₃, —CH₃, —CH₂CH₃, -iPr, -nBu, —CF₃, —OH, —OCH₃, —OCF₃, —OCH₂CH₃,—OCH₂CF₃, -OiPr, -OnBu, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂H, —CH₂CH₂CO₂NH₂,—C(═O)NHCH₂C(═O)OCH₃, —C(═O)NHCH₂C(═O)OH, and —C(═O)NHCH₂CH₂OH.

Embodiments of R^(k)

As used above and herein each instance of R^(k) is, independently,selected from —H, —OH, —OR^(i), —N(R^(k))₂, —C(═O)R^(i),—C(═O)N(R^(k))₂, —CO₂R^(i), —SO₂R^(i), —C(═NR^(k))R^(i),—C(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —SO₂N(R^(k))₂, —SO₂R^(i),—SO₂OR^(i), —SOR^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(m) groups, wherein R^(i), R^(k), R^(m) are as definedabove and herein.

In certain embodiments, each instance of R^(k) is, independently,selected from —H, —C(═O)R^(i), —C(═O)OR^(i), —SO₂R^(i), or C₁₋₆ alkyl.In certain embodiments, each instance of R^(k) is, independently,selected from —H or C₁₋₆ alkyl. In certain embodiments, each instance ofR^(k) is, independently, selected from —H and —CH₃. In certainembodiments, each instance of R^(k) is, independently, selected from —H.In certain embodiments, each instance of R^(k) is, independently,selected from —CH₃.

Groups R^(a), R^(b), and R^(e)

As generally defined above, wherein R^(d) is the group -L-Z, each ofR^(a), R^(b), and R^(e) independently is selected from —H, C₁₋₁₀ alkyland C₁₋₁₀ perhaloalkyl.

In certain embodiments, each of R^(a), R^(b), and R^(c) independently isselected from —H, C₁₋₆ alkyl and C₁₋₆ perhaloalkyl. In certainembodiments, each of R^(a), R^(b), and R^(c) independently is selectedfrom —H, C₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, eachof R^(a), R^(b), and R^(c) independently is selected from —H, —CH₃,—CH₂CH₃ and —CF₃. In certain embodiments, each of R^(a), R^(b), andR^(c) independently is selected from —H, —CH₃, and —CF₃.

In certain embodiments, R^(a) and R^(b) are H and R^(e) is selected fromC₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, R^(a) andR^(b) are H and R^(c) is selected from —CH₃ and —CF₃. In certainembodiments, R^(a) and R^(b) are H and R^(e) is —CH₃. In certainembodiments, R^(a) and R^(b) are H and R^(c) is —CF₃.

In certain embodiments, R^(b) and R^(c) are H and R^(a) is selected fromC₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, R^(b) andR^(c) are H and R^(a) is selected from —CH₃ and —CF₃. In certainembodiments, R^(b) and R^(c) are H and R^(a) is —CH₃. In certainembodiments, R^(b) and R^(c) are H and R^(a) is —CF₃.

In certain embodiments, each of R^(a), R^(b), and R^(c) independently isselected from H, —CH₃ and —CF₃. In certain embodiments, each of R^(a),R^(b), and R^(c) independently is selected from H or —CH₃. In certainembodiments, each of R^(a), R^(b), and R^(e) is H.

Group R^(d)

As generally defined above, in certain embodiments, R^(d) is the group-L-Z,

wherein L is a covalent bond or a divalent C₁₋₆ hydrocarbon group,wherein one, two or three methylene units of L are optionally andindependently replaced with one or more oxygen, sulfur or nitrogenatoms, and Z is selected from C₆₋₁₀ aryl.

Group L of R^(d)

As generally defined above, L is a covalent bond or a divalent C₁₋₆hydrocarbon group, wherein one, two or three methylene units of L areoptionally and independently replaced with one or more oxygen, sulfur ornitrogen atoms.

In certain embodiments, L is a covalent bond.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen (—O—), sulfur (—S—) or nitrogen (e.g.,—NR¹—) atoms.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen (—O—) atoms.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more sulfur (—S—) atoms.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more nitrogen (—NR¹—) atoms. However, in certainembodiments, wherein L is a divalent C₁₋₆ hydrocarbon group comprisingone, two or three nitrogen atoms, then L is an unsubstituted divalentC₁₋₆ hydrocarbon group and L is not the group —CH₂NR¹— wherein R¹ is H,C₁₋₆ alkyl or an amino protecting group.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone methylene unit of L is optionally and independently replaced with anoxygen, sulfur or nitrogen atom. In certain embodiments, L is a divalentC₁₋₆ hydrocarbon group, wherein one methylene unit of L is optionallyand independently replaced with an oxygen atom. In certain embodiments,L is a divalent C₁₋₆ hydrocarbon group, wherein one methylene unit of Lis optionally and independently replaced with a sulfur atom. In certainembodiments, L is a divalent C₁₋₆ hydrocarbon group, wherein onemethylene unit of L is optionally and independently replaced with anitrogen atom.

In certain embodiments of L, the divalent C₁₋₆ hydrocarbon group is anunsubstituted divalent C₁₋₆ hydrocarbon group. In certain embodiments ofL, the divalent C₁₋₆ hydrocarbon group contains one oxygen, sulfur ornitrogen atom. In certain embodiments, the divalent C₁₋₆ hydrocarbongroup is an unsubstituted divalent C₁₋₆ hydrocarbon group (e.g., anunsubstituted divalent C₁₋₆ alkyl group).

For example, in certain embodiments, L is an unsubstituted divalent C₁₋₆alkyl group, wherein one methylene unit of L is replaced with an oxygen,sulfur or nitrogen atom. In certain embodiments, L is an unsubstituteddivalent C₁₋₆ alkyl group, wherein one methylene unit of L is replacedwith an oxygen atom. In certain embodiments, L is an unsubstituteddivalent C₁₋₅alkyl, wherein one methylene unit of L is replaced with asulfur atom. In certain embodiments, L is an unsubstituted divalent C₁₋₆alkyl group, wherein one methylene unit of L is replaced with a nitrogenatom. However, in certain embodiments, wherein L is an unsubstituteddivalent C₁₋₆ alkyl group, then L is not the group —CH₂NR¹— wherein R¹is H, C₁₋₆ alkyl or an amino protecting group.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone methylene unit of L is replaced with an oxygen, sulfur or nitrogenatom, e.g., L is selected from oxygen (—O—), sulfur (—S—) or nitrogen(e.g., —NR¹—). In certain embodiments, L is oxygen (—O—). In certainembodiments, L is sulfur (—S—). In certain embodiments, L is nitrogen(e.g., —NR¹—).

In certain embodiments, L is selected from the group consisting of—(C(R¹⁰)₂)_(m)—, (C(R¹¹)₂)_(m)—O—(C(R¹²)₂)_(n),—(C(R¹¹)₂)_(m)—S—(C(R¹²)₂)_(n)—, or —(C(R¹¹)₂)_(m)—NR¹—(C(R¹²)₂)_(n)—,wherein m and n are, independently, 0, 1, 2, 3, 4, 5 or 6, and eachinstance of R¹⁰, R¹¹ and R¹² are, independently, selected from H,halogen or C₁₋₆ alkyl. In certain embodiments, each of R¹⁰, R¹¹ and R¹²are —H.

In certain embodiments, L is —(C(R¹⁰)₂)_(m)—. In certain embodiments, Lis selected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH₂CH₂—.

In certain embodiments, L is —(C(R¹¹)₂)_(m)—O—(C(R¹²)₂)_(n)—. In certainembodiments, L is selected from —O—, —CH₂O—, —OCH₂—, —OCH₂CH₂—,—OCH₂CH₂—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂OCH₂CH₂—, and —CH₂CH₂OCH₂—.

In certain embodiments, L is —(C(R¹¹)₂)_(m)—S—(C(R¹²)₂)_(n)—. In certainembodiments, L is selected from —S—, —CH₂S—, —SCH₂—, —SCH₂CH₂—,—CH₂CH₂S—, —SCH₂CH₂CH₂—, —CH₂CH₂CH₂S—, —CH₂SCH₂CH₂—, and —CH₂CH₂SCH₂—.

In certain embodiments, L is —(C(R¹¹)₂)_(m)—NR¹—(C(R¹²)₂)_(n)—. Incertain embodiments, L is selected from —NR¹—, —CH₂NR¹—, —NR¹CH₂—,—NR¹CH₂CH₂—, —CH₂CH₂NR¹—, —NR¹CH₂CH₂CH₂—, —CH₂CH₂CH₂NR¹—,—CH₂NR¹CH₂CH₂—, and —CH₂CH₂NR¹CH₂—, wherein R¹ is selected from H, anC₁₋₆ alkyl or an amino protecting group.

In certain embodiments, R¹ is selected from H or C₁₋₆ alkyl. In certainembodiments, R¹ is hydrogen. In certain embodiments, R¹ is —CH₃.

Group Z of R^(d)

As defined generally above, Z is C₆₋₁₄ aryl. In certain embodiments, Zis C₆₋₁₄ aryl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is C₆ aryl (e.g., phenyl) substituted with 0, 1, 2, 3, 4or 5 R¹⁵ groups. In certain embodiments, Z is a C₁₀ aryl (e.g.,naphthyl) substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

In certain embodiments, Z is phenyl. In certain embodiments, Z is phenylsubstituted with 0, 1, 2, 3 or 4 R¹⁵ groups. In certain embodiments, Zis phenyl substituted with 0, 1, 2 or 3 R¹⁵ groups. In certainembodiments, Z is phenyl substituted with 0, 1 or 2 R¹⁵ groups. Incertain embodiments, Z is phenyl substituted with 0 or 1 R¹⁵ groups. Incertain embodiments, Z is a disubstituted phenyl (i.e., substituted with2 R¹⁵ groups). In certain embodiments, Z is a monosubstituted phenyl(i.e., substituted with 1 R¹⁵ group). In certain embodiments, Z is anunsubstituted phenyl (i.e., substituted with 0 R¹⁵ groups).

In certain embodiments, Z is phenyl substituted with at least one orthoR¹⁵ group. In certain embodiments, Z is phenyl substituted with at leastone meta R¹⁵ group. In certain embodiments, Z is phenyl substituted withat least one para R¹⁵ group.

In certain embodiments, Z is a monosubstituted phenyl substituted withone ortho R¹⁵ group. In certain embodiments, Z is a monosubstitutedphenyl substituted with one meta R¹⁵ group. In certain embodiments, Z isa monosubstituted substituted with one para R¹⁵ group.

In certain embodiments, Z is a disubstituted phenyl substituted with anortho R¹⁵ group and a meta R¹⁵ group. In certain embodiments, Z is adisubstituted phenyl substituted with an ortho R¹⁵ group and a para R¹⁵group. In certain embodiments, Z is a disubstituted phenyl substitutedwith a meta R¹⁵ group and a para R¹⁵ group. In certain embodiments, Z isa disubstituted phenyl substituted with two meta R¹⁵ groups.

In certain embodiments, Z is a phenyl group of the formula:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, zis 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certainembodiments, z is 0 or 1. In certain embodiments, z is 3. In certainembodiments, Z is a disubstituted phenyl group (i.e., wherein z is 2).In certain embodiments, Z is a monosubstituted phenyl group (i.e.,wherein z is 1). In certain embodiments, Z is an unsubstituted phenylgroup (i.e., wherein z is 0).

For example, in certain embodiments, Z is a substituted or unsubstitutedphenyl group of an one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a naphthyl. In certain embodiments, Z is anaphthyl group of any one of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, zis 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In certainembodiments, z is 0 or 1. In certain embodiments, Z is a trisubstitutednaphthyl group (i.e., wherein z is 3). In certain embodiments, Z is adisubstituted naphthyl group (i.e., wherein z is 2). In certainembodiments, Z is a monosubstituted naphthyl group (i.e., wherein z is1). In certain embodiments, Z is an unsubstituted naphthyl group (i.e.,wherein z is 0).

For example, in certain embodiments, Z is a substituted or unsubstituted1-naphthyl group of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a substituted or unsubstituted 2-naphthylgroup of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

R¹⁵ Groups

As used herein, each instance of R¹⁵ is, independently, selected fromhalogen (i.e., fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I)),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR¹⁶, —ON(R¹⁸)₂, —N(R¹⁸)₂, —N(R¹⁸)₃⁺X⁻, —N(OR¹⁷)R¹⁸, —SH, —SR¹⁶, —SSR¹⁷, —C(═O)R¹⁶, —CO₂H, —CHO, —CO₂R¹⁶,—OC(═O)R¹⁶, —OCO₂R¹⁶, —C(═O)N(R¹⁸)₂, —OC(═O)N(R¹⁸)₂, —NR¹⁸C(═O)R¹⁶,—NR¹⁸CO₂R¹⁶, —NR¹⁸C(═O)N(R¹⁸)₂, —C(═NR¹⁸)R¹⁶, —C(═NR¹⁸)OR¹⁶,—OC(═NR¹⁸)R¹⁶, —OC(═NR¹⁸)OR¹⁶, —C(═NR¹⁸)N(R¹⁸)₂, —OC(═NR¹⁸)N(R¹⁸)₂,—NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, —C(═O)NR¹⁸SO₂R¹⁶, —NR¹⁸SO₂R¹⁶, —SO₂N(R¹⁸)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —OSO₂R¹⁶, —S(═O)R¹⁶, —OS(═O)R¹⁶, —Si(R¹⁶)₃,—OSi(R¹⁶)₃—C(═S)N(R¹⁸)₂, —C(═O)SR¹⁶, —C(═S)SR¹⁶, —SC(S)SR¹⁶, —P(═O)₂R¹⁶,—OP(═O)₂R¹⁶, —P(═O)(R¹⁶)₂, —OP(═O)(R¹⁶)₂, —OP(═O)(OR¹⁷)₂,—P(═O)₂N(R¹⁸)₂, —OP(═O)₂N(R¹⁸)₂, —P(═O)(NR¹⁸)₂, —OP(═O)(NR¹⁸)₂,—NR18P(═O)(OR¹⁷)₂, —NR¹⁸P(═O)(NR¹⁸)₂, —P(R¹⁷)₂, —P(R¹⁷)₃, —OP(R¹⁷)₂,—OP(R¹⁷)₃, —B(OR¹⁷)₂, —BR¹⁶(OR¹⁷), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; or twovicinal R¹⁵ groups are replaced with the group —O(C(R²)₂)₁₋₂O— whereineach R² is independently H, C₁₋₆alkyl or halogen;

each instance of R¹⁶ is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups;

each instance of R¹⁸ is, independently, selected from hydrogen, —OH,—OR¹⁶, —N(R¹⁷)₂, —CN, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶, —SO₂R¹⁶,—C(═NR¹⁷)OR¹⁶, —C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂, —SO₂R¹⁷, —SO₂OR¹⁷, —SOR¹⁶,—C(═S)N(R¹⁷)₂, —C(═O)SR¹⁷, —C(═S)SR¹⁷, —P(═O)₂R¹⁶, —P(═O)(R¹⁶)₂,—P(═O)₂N(R¹⁷)₂, —P(═O)(NR¹⁷)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R¹⁷ groups attached toan N atom are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups;

each instance of R¹⁷ is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R¹⁷ groups attached to an N atom are joined to form a3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups;

each instance of R¹⁹ is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR²⁰, —ON(R²¹)₂, —N(R²¹)₂, —N(R²¹)₃ ⁺X⁻,—N(OR²⁰)R²¹, —SH, —SR²⁰, —SSR²⁰, —C(═O)R²⁰, —CO₂H, —CO₂R²⁰, —OC(═O)R²⁰,—OCO₂R²⁰, —C(═O)N(R²¹)₂, —OC(═O)N(R²¹)₂, —NR²¹C(═O)R²⁰, —NR²¹CO₂R²⁰,—NR²¹C(═O)N(R²¹)₂, —C(═NR²¹)OR²⁰, —OC(═NR²¹)R²⁰, —OC(═NR²¹)OR²⁰,—C(═NR²¹)N(R²¹)₂, —OC(═NR²¹)N(R²¹)₂, —NR²¹C(═NR²¹)N(R²¹)₂, —NR²¹SO₂R²⁰,—SO₂N(R²¹)₂, —SO₂R²⁰, —SO₂OR²⁰, —OSO₂R²⁰, —S(═O)R²⁰, —Si(R²⁰)₃,—OSi(R²⁰)₃, —C(═S)N(R²¹)₂, —C(═O)SR²⁰, —C(═S)SR²⁰, —SC(═S)SR²⁰,—P(═O)₂R²⁰, —P(═O)(R²⁰)₂, —OP(═O)(R²⁰)₂, —OP(═O)(OR²⁰)₂, C₁₋₆alkyl, C₁₋₆perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R²²groups, or two geminal R¹⁹ substituents can be joined to form ═O or ═S;

each instance of R²⁰ is, independently, selected from C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R²² groups;

each instance of R²¹ is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆-perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R²¹ groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R²² groups; and

each instance of R²² is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆alkyl)X, —NH₃X, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂,—OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆alkyl), —SO₂N(C₁₋₁₆alkyl)₂, —SO₂NH(C₁₋₆alkyl), —SO₂NH₂, —SO₂C₁₋₅ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or twogeminal R²² substituents can be joined to form ═O or ═S;

wherein X⁻ is a counterion.

In certain embodiments, each instance of R¹⁵ is, independently, selectedfrom fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —OR¹⁶,—C(═O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups.

In certain embodiments, R¹⁵ is, independently, selected from fluoro(—F), bromo (—Br), chloro (—Cl), and iodo (—I), —OR¹⁶ and C₁₋₁₀perhaloalkyl. In certain embodiments, R¹⁵ is, independently, selectedfrom fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I) and —OR¹⁶. Incertain embodiments, R¹⁵ is, independently, selected from fluoro (—F),bromo (—Br), chloro (—Cl), and iodo (—I) and C₁₋₁₀ perhaloalkyl.

In certain embodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀perhaloalkyl.

In certain embodiments, R¹⁵ is —OR¹⁶. In certain embodiments, R¹⁶ isselected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with0, 1, 2, 3, 4, or 5 R¹⁹ groups.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₁₋₁₀alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₁₋₆ alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₁₋₄ alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from C₁₋₂alkyl. In certain embodiments, R¹⁵ is —OR¹⁶ and R¹⁶ is—CH₃, -Et, -iPr, -nBu, -n-pentyl. In certain embodiments, R¹⁵ is —OR¹⁶and R¹⁶ is —CH₃.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₁₋₁₀perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₁₋₆ perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from C₁₋₄ perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶,and R¹⁶ is selected from C₁₋₂ perhaloalkyl. In certain embodiments, R¹⁵is —OR¹⁶ and R¹⁶ is —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, or —CF₂Cl.In certain embodiments, R¹⁵ is —OR¹⁶ and R¹⁶ is —CF₃.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₂₋₁₀alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₂₋₆ alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₂₋₄ alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from —CH₂CHCH₂ (i.e., allyl).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₂₋₁₀alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₂₋₆ alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₂₋₄ alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from —CH₂CCH (i.e., propargyl).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₆ aryl(e.g., phenyl) substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certainembodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is phenyl substituted with 0, 1 or 2R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is phenylsubstituted with 1 R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, andR¹⁶ is phenyl substituted with 0 R¹⁹ groups (i.e., —C₆H₅).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from 5-6membered heteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. Incertain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from a 6 memberedheteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certainembodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl)substituted with 0, 1, 2 or 3 R¹⁹ groups.

In certain embodiments, R¹⁵ is —C(═O)N(R⁸)₂.

In certain embodiments, R¹⁵ is —SO₂N(R¹⁸)₂.

In certain embodiments, R¹⁵ is C₁₋₁₀ perhaloalkyl. In certainembodiments, R¹⁵ is C₁₋₆ perhaloalkyl. In certain embodiments, R¹⁵ isC₁₋₄ perhaloalkyl. In certain embodiments, R¹⁵ is C₁₋₂ perhaloalkyl. Incertain embodiments, R¹⁵ is selected from —CF₃, —CF₂CF₃, —CF₂CF₂CF₃,—CCl₃, —CFCl₂, and —CF₂Cl. In certain embodiments, R¹⁵ is selected from—CF₃.

In certain embodiments, R¹⁵ is C₁₋₁₀ alkyl substituted with 0, 1, 2, 3,4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₂₋₆ alkylsubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups. R¹⁵ is C₁₋₄ alkylsubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups. In certain embodiments,the R¹⁵ alkyl group is unsubstituted (0 R¹⁹ groups). In certainembodiments, R¹⁵ is —CH₃, -Et, -iPr, -nBu, -n-pentyl.

In certain embodiments, R¹⁵ is C₂₋₁₀ alkenyl substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₂₋₆ alkenylsubstituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certain embodiments, R¹⁵is C₂₋₄ alkenyl substituted with 0, 1, 2 or 3 R¹⁹ groups. In certainembodiments, the R¹⁵ alkenyl group is unsubstituted (0 R¹⁹ groups). Incertain embodiments, R¹⁵ is —CH₂CHCH₂ (i.e., allyl),

In certain embodiments, R¹⁵ is C₂₋₁₀ alkynyl substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₂₋₆ alkynylsubstituted with 0, 1, 2 or 3 R¹⁹ groups. In certain embodiments, R¹⁵ isC₂₋₄ alkynyl substituted with 0, 1 or 2 R¹⁹ groups. In certainembodiments, the R¹⁵ alkynyl group is unsubstituted (0 R¹⁹ groups). Incertain embodiments, R¹⁵ is —CH₂CCH (i.e., propargyl).

In certain embodiments, R¹⁵ is C₆₋₁₄ aryl. In certain embodiments, R¹⁵is selected from C₆ aryl (e.g., phenyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is an unsubstituted phenyl. Incertain embodiments, R¹⁵ is a monosubstituted phenyl (i.e., substitutedwith 1 R¹⁹ group).

In certain embodiments, R¹⁵ is 5-14 membered heteroaryl substituted with0, 1, 2, 3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is 5-6membered heteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. Incertain embodiments, R¹⁵ is a 6-membered heteroaryl substituted with 0,1, 2, 3 or 4 R¹⁹ groups. In certain embodiments, R¹⁵ is pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2 or3 R¹⁹ groups. In certain embodiments, the R¹⁵ heteroaryl group isunsubstituted (0 R¹⁹ groups).

R¹⁸Groups

In certain embodiments, each instance of R¹⁸ is, independently, selectedfrom —H, —OH, —OR¹⁶, —N(R⁷)₂, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶,—SO₂R¹⁶, —C(═NR¹⁷)R¹⁶, —C(═NR¹⁷)OR¹⁶, —C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —SOR¹⁶, —C(═S)N(R¹⁷)₂, —C(═O)SR16, —C(═S)SR¹⁶, C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups, wherein R¹⁶, R¹⁷, R¹⁹ are as defined above andherein.

In certain embodiments, each instance of R¹⁷ is, independently, selectedfrom —H, —C(═O)R¹⁶, —C(═O)OR¹⁶, —SO₂R¹⁶, or C₁₋₆ alkyl. In certainembodiments, each instance of R¹⁷ is, independently, selected from —H orC₁₋₆ alkyl. In certain embodiments, each instance of R¹⁷ is,independently, selected from —H and —CH₃. In certain embodiments, eachinstance of R¹⁷ is, independently, selected from —H. In certainembodiments, each instance of R¹⁷ is, independently, selected from —CH₃.

Additional Embodiments of Compounds of Formula (I)

As defined generally above, the present invention provides compounds ofthe formula (I):

or a pharmaceutically acceptable form thereof, wherein G, R^(a), R^(b),R^(e) and R^(d) are as defined herein.

In one aspect, wherein R^(a), R^(b), R^(c) are each H, and R^(d) is thegroup Z, the present invention provides compounds of the formula (II):

or a pharmaceutically acceptable form thereof, wherein G and Z are asdefined herein. In certain embodiments, L is a covalent bond. In certainembodiments, G is —OR^(e). In certain embodiments, G is —Br. However, incertain embodiments, G is not halogen (e.g., —Br, —Cl, —I).

For example, in certain embodiments, wherein L is a covalent bond,R^(a), R^(b), R^(c) are each H, and G is the group —OR^(e), the presentinvention provides compounds of the formula (II-a):

or a pharmaceutically acceptable form thereof, wherein R^(e) and Z areas defined herein.

In certain embodiments, wherein Z is a phenyl ring, the presentinvention provides compounds of the formula (II-b):

or a pharmaceutically acceptable form thereof, wherein G, L, R^(a),R^(b), R^(c), R¹⁵ and z are as defined herein. For example, in certainembodiments, z is 1 and R¹⁵ is at the ortho position. In certainembodiments, z is 1 and R¹⁵ is at the meta position. In certainembodiments, z is 1 and R¹⁵ is at the para position. In certainembodiments, z is 2 and R¹⁵ is at the meta and para position. In certainembodiments, L is a covalent bond. In certain embodiments, G is —OR^(e).In certain embodiments, G is —Br. However, in certain embodiments, G isnot halogen (e.g., —Br, —Cl, —I). In certain embodiments, R¹⁵ isselected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl.

For example, in certain embodiments, z is 1 and R¹⁵ is para to providecompounds of the formula (II-c):

or a pharmaceutically acceptable form thereof, wherein G, L, R^(a),R^(b), R^(c), R¹⁵ and z are as defined herein. In certain embodiments, Lis a covalent bond. In certain embodiments, G is —OR^(e). In certainembodiments, G is —Br. However, in certain embodiments, G is not halogen(e.g., —Br, —Cl, —I). In certain embodiments, R¹⁵ is selected from —OR¹⁶and C₁₋₁₀ perhaloalkyl.

For example, in certain embodiments, z is 2 and one R⁵ is meta and oneR⁵ is para to provide compounds of the formula (II-c):

or a pharmaceutically acceptable form thereof, wherein G, L, R^(a),R^(b), R^(c), R¹⁵ and z are as defined herein. In certain embodiments, Lis a covalent bond. In certain embodiments, G is —OR^(e). In certainembodiments, G is —Br. However, in certain embodiments, G is not halogen(e.g., —Br, —Cl, —I). In certain embodiments, R¹⁵ is selected from —OR¹⁶and C₁₋₁₀ perhaloalkyl.

For example, in certain embodiments, wherein Z is an phenyl ring, and Gis the group —OR^(e), the present invention provides compounds of theformula (II-d):

or a pharmaceutically acceptable form thereof, wherein L, R^(a), R^(b),R^(c), R¹⁵, R^(e) and z are as defined herein. For example, in certainembodiments, z is 1 and R¹⁵ is at the ortho position. In certainembodiments, z is 1 and R¹⁵ is at the meta position. In certainembodiments, z is 1 and R¹⁵ is at the para position. In certainembodiments, L is a covalent bond. In certain embodiments, R¹⁵ isselected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl.

In certain embodiments, wherein Z is an phenyl ring, G is the group—OR^(e), and R^(e) is an phenyl ring, the present invention providescompounds of the formula (II-e):

or a pharmaceutically acceptable form thereof, wherein L, R^(a), R^(b),R^(c), R¹⁵, R^(h), x and z are as defined herein. For example, incertain embodiments, z is 1 and R¹⁵ is at the ortho position. In certainembodiments, z is 1 and R¹⁵ is at the meta position. In certainembodiments, z is 1 and R¹⁵ is at the para position. In certainembodiments, L is a covalent bond. In certain embodiments, R¹⁵ isselected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl.

In certain embodiments, wherein Z is an phenyl ring, G is the group—OR^(e), and R^(e) is an 5-membered heteroaryl ring, the presentinvention provides compounds of the formula (II-f):

or a pharmaceutically acceptable form thereof, wherein Y^(a), Y^(b),Y^(c), Y^(d), L, R^(a), R^(b), R^(c), R¹⁵ and z are as defined herein.For example, in certain embodiments, z is 1 and R¹⁵ is at the orthoposition. In certain embodiments, z is 1 and R¹⁵ is at the metaposition. In certain embodiments, z is 1 and R¹⁵ is at the paraposition. In certain embodiments, L is a covalent bond. In certainembodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl.

In certain embodiments, wherein Z is an phenyl ring, G is the group—OR^(e), and R^(e) is an 6-membered heteroaryl ring, the presentinvention provides compounds of the formula (II-g):

or a pharmaceutically acceptable form thereof, wherein W^(a), W^(b),W^(c), W^(d), W^(e), L, R^(a), R^(b), R^(e), R¹⁵ and z are as definedherein. For example, in certain embodiments, z is 1 and R¹⁵ is at theortho position. In certain embodiments, z is 1 and R¹⁵ is at the metaposition. In certain embodiments, z is 1 and R¹⁵ is at the paraposition. In certain embodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀perhaloalkyl. In certain embodiments, L is a covalent bond. In certainembodiments, W^(b) is N and W^(a), W^(e), W^(d) and W^(e) are selectedfrom CH or CR^(h). In certain embodiments, In certain embodiments, W^(b)is N, W^(e) is CR^(h) and W^(a), W^(e), W^(d) and W^(e) are each CH. Incertain embodiments, W^(b) and W^(d) are N and Wa, We, W^(d) and W^(e)are selected from CH or CR^(h)

In certain embodiments, wherein Z is a phenyl ring, G is the group—OR^(e), and R^(e) is an 9-membered heteroaryl ring, the presentinvention provides compounds of the formula (II-h):

or a pharmaceutically acceptable form thereof, wherein Y^(e), Y^(f),Y^(g), Y^(i), Y^(j), Y^(k), Y^(k), Y^(n), L, R^(a), R^(b), R^(c), R¹⁵and z are as defined herein. For example, in certain embodiments, z is 1and R¹⁵ is at the ortho position. In certain embodiments, z is 1 and R¹⁵is at the meta position. In certain embodiments, z is 1 and R¹⁵ is atthe para position. In certain embodiments, R¹⁵ is selected from —OR¹⁶and C₁₋₁₀ perhaloalkyl. In certain embodiments, L is a covalent bond.

In certain embodiments, wherein Z is a phenyl ring, G is the group—OR^(e), and R^(e) is an 10-membered heteroaryl ring, the presentinvention provides compounds of the formula (II-i):

or a pharmaceutically acceptable form thereof,

wherein W^(f), W^(g), W^(h), W^(i), W^(j), W^(k), W^(m), W^(n), L,R^(a), R^(b), R^(c), R¹⁵ and z are as defined herein. For example, incertain embodiments, z is 1 and R¹⁵ is at the ortho position. In certainembodiments, z is 1 and R¹⁵ is at the meta position. In certainembodiments, z is 1 and R¹⁵ is at the para position. In certainembodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl. Incertain embodiments, L is a covalent bond.

In certain embodiments, wherein Z is a phenyl ring, and G is the group—NR^(e)R^(f), the present invention provides compounds of the formula(II-j):

or a pharmaceutically acceptable form thereof, wherein L, R^(a), R^(b),R^(c), R^(e), R^(f), R¹⁵ and z are as defined herein. For example, incertain embodiments, z is 1 and R¹⁵ is at the ortho position. In certainembodiments, z is 1 and R¹⁵ is at the meta position. In certainembodiments, z is 1 and R¹⁵ is at the para position. In certainembodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀ perhaloalkyl. Incertain embodiments, L is a covalent bond. In certain embodiments, R^(e)and R^(f) are joined to form a 3-10 membered heterocycyl ring. Incertain embodiments, R^(e) and R^(f) are joined to form a 5-14 memberedheteroaryl ring.

Exemplary Compouds of the Present Invention

Exemplary compounds of formulae (I), (II), and subgenera thereof, areset forth in the Tables 1a-1m below, and are also described in moredetail in Examples 1-253, provided herein, Compounds were assayed asinhibitors of human FAAH using the Method described in detail in Example254.

In certain embodiments, the compound is any one of the compoundsprovided in Table 1a, or a pharmaceutically acceptable form thereof:

TABLE 1a

Com- pound G R^(a) R^(c) I-10 —Br —H —H I-17 —Cl —H —H I-23

—H —H I-24

—H —H I-25

—H —H I-26

—H —H I-27

—H —H I-28

—H —H I-29

—H —H I-30

—H —H I-31

—H —H I-32

—H —H I-33

—H —H I-34

—H —H I-35

—H —H I-36

—H —H I-37

—H —H I-39

—H —H I-40

—H —H I-41

—H —H I-42

—H —H I-43

—H —H I-44

—H —H I-45 —OMe —H —H I-47

—H —H I-56

—H —H I-57

—H —H I-58

—H —H I-59

—H —H I-60

—H —H I-61

—H —H I-62

—H —H I-63

—H —H I-64

—H —H I-65

—H —H I-66

—H —H I-67

—H —H I-68

—H —H I-69

—H —H I-90

—H —H I-92

—H —H I-93

—H —H I-94

—H —H I-98

—H —H I-99

—H —H I-100

—H —H I-110

—H —H I-111

—H —H I-146

—H —H I-147

—H —H I-155

—H —H I-159

—H —H I-160

—H —H I-197

—H —H I-243

—H —H I-244

—H —H I-245

—H —H I-256

—H —H I-257

—H —H I-260

—H —H I-78 —Br —CH₃ —H (cis) I-82 —Br —CH₃ —H (trans) I-91 (trans)

—CH₃ —H I-76 —Br —H —CH₃ I-89

—H —CH₃ I-130 —Br —H —CF₃ I-131

—H —CF₃ I-95 —Br —H —CH₂CH₃

In certain embodiments, the compound is any one of the compoundsprovided in Table 1b, or a pharmaceutically acceptable form thereof:

TABLE 1b

Com- pound G R^(a) R^(c) I-14 —Br —H —H I-46

—H —H I-53

—H —H I-54

—H —H I-55

—H —H I-70

—H —H I-71

—H —H I-72

—H —H I-73

—H —H I-83

—H —H I-84

—H —H I-85

—H —H I-86

—H —H I-96

—H —H I-97

—H —H I-105

—H —H I-106

—H —H I-107

—H —H I-108

—H —H I-109

—H —H I-112

—H —H I-118

—H —H I-128

—H —H I-132

—H —H I-133

—H —H I-134

—H —H I-135

—H —H I-136

—H —H I-151

—H —H I-152

—H —H I-157

—H —H I-161

—H —H I-162

—H —H I-163

—H —H I-165

—H —H I-173

—H —H I-174

—H —H I-175

—H —H I-176

—H —H I-177

—H —H I-178

—H —H I-182

—H —H I-183

—H —H I-184

—H —H I-186

—H —H I-187

—H —H I-188

—H —H I-189

—H —H I-190

—H —H I-191

—H —H I-192

—H —H I-193

—H —H I-194

—H —H I-195

—H —H I-199

—H —H I-200

—H —H I-201

—H —H I-218

—H —H I-220

—H —H I-221

—H —H I-223

—H —H I-224

—H —H I-225

—H —H I-226

—H —H I-230

—H —H I-236

—H —H I-246

—H —H I-248

—H —H I-249

—H —H I-250

—H —H I-251

—H —H I-253

—H —H I-255

—H —H I-258

—H —H I-75 —Br —H —CH₃ I-88

—H —CH₃ I-113

—H —CH₃ I-114

—H —CH₃ I-115

—H —CH₃ I-116

—H —CH₃ I-117

—H —CH₃ I-129

—H —CH₃ I-154

—H —CH₃ I-156

—H —CH₃ I-158

—H —CH₃ I-164

—H —CH₃ I-167

—H —CH₃ I-171

—H —CH₃ I-172

—H —CH₃ I-185

—H —CH₃ I-196

—H —CH₃ I-198

—H —CH₃ I-222

—H —CH₃ I-227

—H —CH₃ I-228

—H —CH₃ I-229

—H —CH₃ I-231

—H —CH₃ I-232

—H —CH₃ I-233

—H —CH₃ I-234

—H —CH₃ I-235

—H —CH₃ I-240

—H —CH₃ I-241

—H —CH₃ I-242

—H —CH₃ I-261

—H —CH₃

In certain embodiments, the compound is any one of the compoundsprovided in Table 1c, or a pharmaceutically acceptable form thereof:

TABLE 1c

Compound G R^(a) R^(c) I-168

—H —H I-169

—H —H I-170

—H —H I-216

—H —H I-217

—H —H I-218

—H —H I-238

—H —H I-259

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1d, or a pharmaceutically acceptable form thereof:

TABLE 1d

R¹⁵ = Compound G R^(a) R^(c) halogen I-120 —Br —H —H —F I-121

—H —H —F I-122

—H —H —F I-123

—H —H —F I-124 —Br —H —H —Cl I-125

—H —H —Cl

In certain embodiments, the compound is any one of the compoundsprovided in Table 1e, or a pharmaceutically acceptable form thereof:

TABLE 1e

R¹⁶ = unsubstituted Compound G R^(a) R^(c) alkyl, alkynyl I-142 —Br —H—H

I-143

—H —H

I-144

—H —H

I-145

—H —H

I-140

—H —H

I-141

—H —H

I-15 —Br —H —H

I-137

—H —H n-butyl I-138

—H —H n-butyl I-139

—H —H n-butyl I-6 —Br —H —H —CH₃ I-38

—H —H —CH₃ I-77 —Br —CH₃ —H —CH₃ (trans)

In certain embodiments, the compound is any one of the compoundsprovided in Table 1f, or a pharmaceutically acceptable form thereof:

TABLE 1f

Com- R¹⁵ = pound G R^(a) R^(c) alkyl, aryl I-20 —Br —H —H n-butyl I-180

—H —H n-butyl I-181

—H —H n-butyl I-179 —Br —H —H n-pentyl I-102 —Br —H —CH₃ —C₆H₅ I-104

—H —CH₃ —C₆H₅ I-9 —Br —H —H —C₆H₅ I-101

—H —H —C₆H₅ I-103

—H —H —C₆H₅

In certain embodiments, the compound is any one of the compoundsprovided in Table 1g, or a pharmaceutically acceptable form thereof:

TABLE 1g

Compound G R¹⁵ = halogen I-3 —Br —Cl I-153

—Cl I-148 —Br —Br I-149

—Br I-150

—Br I-237

—Br I-2 —Br —F

In certain embodiments, the compound is any one of the compoundsprovided in Table 1h, or a pharmaceutically acceptable form thereof:

TABLE 1h

Compound G R^(a) R^(c) I-12 —Br —H —H I-87

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1i, or a pharmaceutically acceptable form thereof:

TABLE 1i

Compound G R^(a) R^(c) I-1  —Br —H —H I-166

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1j, or a pharmaceutically acceptable form thereof:

TABLE 1j

Compound G R^(a) R^(c) R² = H, halogen I-126 —Br —H —H —F, —F I-127

—H —H —F, —F I-16  —Br —H —H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1k, or a pharmaceutically acceptable form thereof:

TABLE 1k

Compound G R^(a) R^(c) R¹⁸ I-22  —Br —H —H H, —CH₂Ph I-214

—H —H H, —CH₂Ph I-215

—H —H H, —CH₂Ph I-203 —Br —H —H —CH₃, —CH₃ I-212

—H —H —CH₃, —CH₃ I-202 —Br —H —H

I-204 —Br —H —H —H, —CH₃ I-208 —Br

I-209 —Br —H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1l, or a pharmaceutically acceptable form thereof:

TABLE 1l

Compound G R^(a) R^(c) R¹⁸ I-205 —Br —H —H

I-207 —Br —H —H —H, —CH₃ I-206 —Br —H —H —CH₃, —CH₃ I-210 —Br —H —H

I-211 —Br —H —H

I-213

—H —H —CH₃, —CH₃

In certain embodiments, the compound is any one of the compoundsprovided in Table 1m, or a pharmaceutically acceptable form thereof:

TABLE 1m

I-4

I-5

I-7

I-8

I-11

I-13

I-119

I-18

I-19

I-21

I-48

I-49

I-50

I-51

I-52

I-74

However, in certain embodiments of formulae (I) and (II), or subgenerathereof, any one of the following compounds is specifically excluded:

II. Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of the formula (I) or apharmaceutically acceptable form thereof, and a pharmaceuticallyacceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations in theformulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21^(st) Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the active ingredient intoassociation with a carrier and/or one or more other accessoryingredients, and then, if necessary and/or desirable, shaping and/orpackaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20],polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate[Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate[Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitanmonooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylenemonostearate [Myrj 45], polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether[Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, etc. and/or combinationsthereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutical composition ofthe invention. Another formulation suitable for intranasaladministration is a coarse powder comprising the active ingredient andhaving an average particle from about 0.2 to 500 micrometers. Such aformulation is administered. by rapid inhalation through the nasalpassage from a container of the powder held close to the nares.

Formulations suitable for nasal administration may, for example,comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) ofthe active ingredient, and may comprise one or more of the additionalingredients described herein. A pharmaceutical composition of theinvention can be prepared, packaged, and/or sold in a formulationsuitable for buccal administration. Such formulations may, for example,be in the form of tablets and/or lozenges made using conventionalmethods, and may contain, for example, 0.1 to 20% (w/w) activeingredient, the balance comprising an orally dissolvable and/ordegradable composition and, optionally, one or more of the additionalingredients described herein. Alternately, formulations suitable forbuccal administration may comprise a powder and/or an aerosolized and/oratomized solution and/or suspension comprising the active ingredient.Such powdered, aerosolized, and/or aerosolized formulations, whendispersed, may have an average particle and/or droplet size in the rangefrom about 0.1 to about 200 nanometers, and may further comprise one ormore of the additional ingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for ophthalmic administration.Such formulations may, for example, be in the form of eye dropsincluding, for example, a 0.1/1.0% (w/w) solution and/or suspension ofthe active ingredient in an aqueous or oily liquid carrier. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

Still further encompassed by the invention are pharmaceutical packsand/or kits. Pharmaceutical packs and/or kits provided may comprise aprovided composition and a container (e.g., a vial, ampoule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a suitable aqueous carrier for dilution orsuspension of the provided composition for preparation of administrationto a subject. In some embodiments, contents of provided formulationcontainer and solvent container combine to form at least one unit dosageform.

In some embodiments, a provided composition of the invention can beuseful in conjunction with subject controlled analgesia (PCA) devices,wherein a subject can administer, for example, opioid analgesia asrequired for pain management.

Optionally, a single container may comprise one or more compartments forcontaining a provided composition, and/or appropriate aqueous carrierfor suspension or dilution. In some embodiments, a single container canbe appropriate for modification such that the container may receive aphysical modification so as to allow combination of compartments and/orcomponents of individual compartments. For example, a foil or plasticbag may comprise two or more compartments separated by a perforated sealwhich can be broken so as to allow combination of contents of twoindividual compartments once the signal to break the seal is generated.A pharmaceutical pack or kit may thus comprise such multi-compartmentcontainers including a provided composition and appropriate solventand/or appropriate aqueous carrier for suspension.

Optionally, instructions for use are additionally provided in such kitsof the invention. Such instructions may provide, generally, for example,instructions for dosage and administration. In other embodiments,instructions may further provide additional detail relating tospecialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination withadditional therapy. In one non-limiting example, the formulations of theinvention can be used in conjunction with opioid analgesiaadministration, which may, optionally, comprise use of a subjectcontrolled analgesia (PCA) device. Thus, instructions for use ofprovided formulations may comprise instructions for use in conjunctionwith PCA administration devices.

III. Methods of Use and Treatment

The present invention provides methods for treating a FAAH-mediatedcondition comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable form thereof.

The present invention also provides methods for inhibiting FAAH in asubject comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable form thereof.

The present invention also provides a method of inhibiting activation ofthe FAAH pathway in vitro or ex vivo, comprising contacting a FAAHprotein with a compound of formula (I) in an amount sufficient to reducethe activation of the FAAH pathway.

The present invention also provides use of a compound of formula (I) forthe treatment of a FAAH-mediated condition in a subject.

The present invention also provides use of a compound of formula (I) inthe manufacture of a medicament. In certain embodiments, the medicamentis useful for treating a FAAH-mediated condition.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, and/or turkeys.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from the specified disease, disorder orcondition, which inhibits or reduces the severity of the disease,disorder or condition.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease, disorder or condition in a subject who has alreadysuffered from the disease, disorder or condition, and/or lengthening thetime that a subject who has suffered from the disease, disorder orcondition remains in remission. The terms encompass modulating thethreshold, development and/or duration of the disease, disorder orcondition, or changing the way that a subject responds to the disease,disorder or condition.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease,disorder or condition, or to delay or minimize one or more symptomsassociated with the disease, disorder or condition. A therapeuticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment or management of the disease,disorder or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease or condition, or enhances the therapeuticefficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

As used herein “inhibition”, “inhibiting”, “inhibit” and “inhibitor”,and the like, refer to the ability of a compound to reduce, slow, haltor prevent activity of a particular biological process (e.g., FAAHactivity) in a cell relative to vehicle.

“FAAH-mediated condition” as used herein, refers to a disease, disorderor condition which is treatable by inhibition of FAAH activity.“Disease”, “disorder” or “condition” are terms used interchangeablyherein. FAAH-mediated conditions include, but are not limited to,painful conditions, inflammatory conditions, immune disorders, disordersof the central nervous system, metabolic disorders, cardiac disordersand glaucoma.

In certain embodiments, the FAAH-mediated condition is a painfulcondition. As used herein, a “painful condition” includes, but is notlimited to, neuropathic pain (e.g., peripheral neuropathic pain),central pain, deafferentiation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain, e.g., pain arising after hip, knee, or other replacement surgery),pre-operative pain, stimulus of nociceptive receptors (nociceptivepain), acute pain (e.g., phantom and transient acute pain),non-inflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, post-operative pain, pain associated with medicalprocedures, pain resulting from pruritus, painful bladder syndrome, painassociated with premenstrual dysphoric disorder and/or premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with drawl symptoms from drugaddiction, joint pain, arthritic pain (e.g., pain associated withcrystalline arthritis, osteoarthritis, psoriatic arthritis, goutyarthritis, reactive arthritis, rheumatoid arthritis or Reiter'sarthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine,muscle ache, lower back pain, neck pain, toothache, dental/maxillofacialpain, visceral pain and the like.

One or more of the painful conditions contemplated herein can comprisemixtures of various types of pain provided above and herein (e.g.nociceptive pain, inflammatory pain, neuropathic pain, etc.). In someembodiments, a particular pain can dominate. In other embodiments, thepainful condition comprises two or more types of pains without onedominating. A skilled clinician can determine the dosage to achieve atherapeutically effective amount for a particular subject based on thepainful condition.

In certain embodiments, the painful condition is neuropathic pain. Theterm “neuropathic pain” refers to pain resulting from injury to a nerve.Neuropathic pain is distinguished from nociceptive pain, which is thepain caused by acute tissue injury involving small cutaneous nerves orsmall nerves in muscle or connective tissue. Neuropathic pain typicallyis long-lasting or chronic and often develops days or months followingan initial acute tissue injury. Neuropathic pain can involve persistent,spontaneous pain as well as allodynia, which is a painful response to astimulus that normally is not painful. Neuropathic pain also can becharacterized by hyperalgesia, in which there is an accentuated responseto a painful stimulus that usually is trivial, such as a pin prick.Neuropathic pain conditions can develop following neuronal injury andthe resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury may occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain conditions include, but are not limited to, diabeticneuropathy (e.g., peripheral diabetic neuropathy); sciatica;non-specific lower back pain; multiple sclerosis pain; carpal tunnelsyndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g.,post-herpetic neuralgia, trigeminal neuralgia); pain resulting fromphysical trauma (e.g., amputation; surgery, invasive medical procedures,toxins, burns, infection), pain resulting from cancer or chemotherapy(e.g., chemotherapy-induced pain such as chemotherapy-induced peripheralneuropathy), and pain resulting from an inflammatory condition (e.g., achronic inflammatory condition). Neuropathic pain can result from aperipheral nerve disorder such as neuroma; nerve compression; nervecrush, nerve stretch or incomplete nerve transsection; mononeuropathy orpolyneuropathy. Neuropathic pain can also result from a disorder such asdorsal root ganglion compression; inflammation of the spinal cord;contusion, tumor or hemisection of the spinal cord; tumors of thebrainstem, thalamus or cortex; or trauma to the brainstem, thalamus orcortex.

The symptoms of neuropathic pain are heterogeneous and are oftendescribed as spontaneous shooting and lancinating pain, or ongoing,burning pain. In addition, there is pain associated with normallynon-painful sensations such as “pins and needles” (paraesthesias anddysesthesias), increased sensitivity to touch (hyperesthesia), painfulsensation following innocuous stimulation (dynamic, static or thermalallodynia), increased sensitivity to noxious stimuli (thermal, cold,mechanical hyperalgesia), continuing pain sensation after removal of thestimulation (hyperpathia) or an absence of or deficit in selectivesensory pathways (hypoalgesia).

In certain embodiments, the painful condition is non-inflammatory pain.The types of non-inflammatory pain include, without limitation,peripheral neuropathic pain (e.g., pain caused by a lesion ordysfunction in the peripheral nervous system), central pain (e.g., paincaused by a lesion or dysfunction of the central nervous system),deafferentation pain (e.g., pain due toloss of sensory input to thecentral nervous system), chronic nociceptive pain (e.g., certain typesof cancer pain), noxious stimulus of nociceptive receptors (e.g., painfelt in response to tissue damage or impending tissue damage), phantompain (e.g., pain felt in a part of the body that nolonger exists, suchas a limb that has been amputated), pain felt by psychiatric subjects(e.g., pain where no physical cause may exist), and wandering pain(e.g., wherein the pain repeatedly changes location in the body).

In certain embodiments, the painful condition is inflammatory pain. Incertain embodiments, the painful condition (e.g., inflammatory pain) isassociated with an inflammatory condition and/or an immune disorder.

In certain embodiments, the FAAH-mediated condition is an inflammatorycondition. The term “inflammatory condition” refers to those diseases,disorders or conditions that are characterized by signs of pain (dolor,from the generation of noxious substances and the stimulation ofnerves), heat (calor, from vasodilatation), redness (rubor, fromvasodilatation and increased blood flow), swelling (tumor, fromexcessive inflow or restricted outflow of fluid), and/or loss offunction (functio laesa, which can be partial or complete, temporary orpermanent. Inflammation takes on many forms and includes, but is notlimited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic,diffuse, disseminated, exudative, fibrinous, fibrosing, focal,granulomatous, hyperplastic, hypertrophic, interstitial, metastatic,necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative inflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), ankylosing spondylitis, amylosis, amyotrophiclateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis,conjunctivitis, Chagas disease, chronic obstructive pulmonary disease,cermatomyositis, diverticulitis, diabetes (e.g., type I diabetesmellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis,eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, reperfusioninjury, regional enteritis, rheumatic fever, systemic lupuserythematosus, schleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds may also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia. The compounds may also be useful in treatinginflammation associated with cancer.

In certain embodiments, the FAAH-mediated condition is an immunedisorder. Immune disorders, such as auto-immune disorders, include, butare not limited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrontestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In certain embodiments, the FAAH-mediated condition is a disorder of thecentral nervous system (CNS) (“CNS disorder”). Exemplary CNS disordersinclude, but are not limited to, neurotoxicity and/or neurotrauma,stroke, multiple sclerosis, spinal cord injury, epilepsy, a mentaldisorder, a sleep condition, a movement disorder, nausea and/or emesis,amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.

In certain embodiments, the CNS disorder is neurotoxicity and/orneurotrauma, e.g., for example, as a result of acute neuronal injury(e.g., tramatic brain injury (TBI), stroke, epilepsy) or a chronicneurodegenerative disorder (e.g., multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis,Alzheimer's disease). In certain embodiments, the compound of thepresent invention provides a neuroprotective effect, e.g., against anacute neuronal injury or a chronic neurodegenerative disorder.

In certain embodiments, the CNS disorder is stroke (e.g., ischemicstroke).

In certain embodiments, the CNS disorder is multiple sclerosis.

In certain embodiments, the CNS disorder is spinal cord injury.

In certain embodiments, the CNS disorder is epilepsy.

In certain embodiments, the CNS disorder is a mental disorder, e.g., forexample, depression, anxiety or anxiety-related conditions, a learningdisability or schizophrenia.

In certain embodiments, the CNS disorder is depression. “Depression,” asused herein, includes, but is not limited to, depressive disorders orconditions, such as, for example, major depressive disorders (e.g.,unipolar depression), dysthymic disorders (e.g., chronic, milddepression), bipolar disorders (e.g., manic-depression), seasonalaffective disorder, and/or depression associated with drug addiction(e.g., withdrawal). The depression can be clinical or subclinicaldepression. The depression can be associated with or prementrualsyndrome and/or premenstrual dysphoric disorder.

In certain embodiments, the CNS disorder is anxiety. “Anxiety,” as usedherein, includes, but is not limited to anxiety and anxiety-relatedconditions, such as, for example, clinical anxiety, panic disorder,agoraphobia, generalized anxiety disorder, specific phobia, socialphobia, obsessive-compulsive disorder, acute stress disorder,post-traumatic stress disorder, adjustment disorders with anxiousfeatures, anxiety disorder associated with depression, anxiety disorderdue to general medical conditions, and substance-induced anxietydisorders, anxiety associated with drug addiction (e.g., withdrawal,dependence, reinstatement) and anxiety associated with nausea and/oremesis. This treatment may also be to induce or promote sleep in asubject (e.g., for example, a subject with anxiety).

In certain embodiments, the CNS disorder is a learning disorder (e.g.,attention deficit disorder (ADD)).

In certain embodiments, the CNS disorder is Schizophrenia.

In certain embodiments, the CNS disorder is a sleep condition. “Sleepconditions” include, but are not limited to, insomia, narcolepsy, sleepapnea, restless legs syndrome (RLS), delayed sleep phase syndrome(DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapideye movement behavior disorder (RBD), shift work sleep condition (SWSD),and sleep problems (e.g., parasomnias) such as nightmares, nightterrors, sleep talking, head banging, snoring, and clenched jaw and/orgrinding of teeth (bruxism).

In certain embodiments, the CNS disorder is a movement disorder, e.g.,basal ganglia disorders, such as, for example, Parkinson's disease,levodopa-induced dyskinesia, Huntington's disease, Gilles de laTourette's syndrome, tardive diskinesia and dystonia.

In certain embodiments, the CNS disorder is Alzheimer's disease.

In certain embodiments, the CNS disorder is amyotrophic lateralsclerosis (ALS).

In certain embodiments, the CNS disorder is nausea and/or emesis.

In certain embodiments, the CNS disorder is drug addiction (e.g., forinstance, addiction to opiates, nicotine, cocaine, psychostimulants oralcohol).

In still yet other embodiments, the FAAH-mediated condition is a cardiacdisorder, e.g., for example, selected from hypertension, circulatoryshock, myocardial reperfusion injury and atherosclerosis.

In certain embodiments, the FAAH-mediated condition is a metabolicdisorder (e.g., a wasting condition, an obesity-related condition orcomplication thereof).

In certain embodiments, the metabolic disorder is a wasting condition. A“wasting condition,” as used herein, includes but is not limited to,anorexia and cachexias of various natures (e.g., weight loss associatedwith cancer, weight loss associated with other general medicalconditions, weight loss associated with failure to thrive, and thelike).

In certain embodiments, the metabolic disorder is an obesity-relatedcondition or a complication thereof. An “obesity-related condition” asused herein, includes, but is not limited to, obesity, undesired weightgain (e.g., from medication-induced weight gain, from cessation ofsmoking) and an over-eating disorder (e.g., binge eating, bulimia,compulsive eating, or a lack of appetite control each of which canoptionally lead to undesired weight gain or obesity). “Obesity” and“obese” as used herein, refers to class I obesity, class II obesity,class III obesity and pre-obesity (e.g., being “over-weight”) as definedby the World Health Organization.

Reduction of storage fat is expected to provide various primary and/orsecondary benefits in a subject (e.g., in a subject diagnosed with acomplication associated with obesity) such as, for example, an increasedinsulin responsiveness (e.g., in a subject diagnosed with Type IIdiabetes mellitus); a reduction in elevated blood pressure; a reductionin elevated cholesterol levels; and/or a reduction (or a reduced risk orprogression) of ischemic heart disease, arterial vascular disease,angina, myocardial infarction, stroke, migraines, congestive heartfailure, deep vein thrombosis, pulmonary embolism, gall stones,gastroesophagael reflux disease, obstructive sleep apnea, obesityhypoventilation syndrome, asthma, gout, poor mobility, back pain,erectile dysfunction, urinary incontinence, liver injury (e.g., fattyliver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediatedliver injury) or chronic renal failure. Thus, the method of thisinvention is applicable to obese subjects, diabetic subjects, andalcoholic subjects.

In some embodiments, treatment of an obesity-related condition orcomplication thereof involves reduction of body weight in the subject.In some embodiments, treatment of an obesity-related condition orcomplication thereof involves appetite control in the subject.

In other embodiments, the FAAH-mediated condition is glaucoma.

IV. Administration

Provided compounds can be administered using any amount and any route ofadministration effective for treatment. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularcomposition, its mode of administration, its mode of activity, and thelike.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease, disorder, or conditionbeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The compounds and compositions provided herein can be administered byany route, including oral, intravenous, intramuscular, intra-arterial,intramedullary, intrathecal, subcutaneous, intraventricular,transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical(as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal,enteral, sublingual; by intratracheal instillation, bronchialinstillation, and/or inhalation; and/or as an oral spray, nasal spray,and/or aerosol. Specifically contemplated routes are systemicintravenous injection, regional administration via blood and/or lymphsupply, and/or direct administration to an affected site. In general themost appropriate route of administration will depend upon a variety offactors including the nature of the agent (e.g., its stability in theenvironment of the gastrointestinal tract), the condition of the subject(e.g., whether the subject is able to tolerate oral administration),etc.

The exact amount of a compound required to achieve a therapeuticallyeffective amount will vary from subject to subject, depending, forexample, on species, age, and general condition of a subject, severityof the side effects or disorder, identity of the particular compound(s),mode of administration, and the like. The desired dosage can bedelivered three times a day, two times a day, once a day, every otherday, every third day, every week, every two weeks, every three weeks, orevery four weeks. In certain embodiments, the desired dosage can bedelivered using multiple administrations (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, ormore administrations).

In certain embodiments, a therapeutically effective amount of a compoundfor administration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of an inventive compound perunit dosage form. It will be appreciated that dose ranges as describedherein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compound or composition can beadministered concurrently with, prior to, or subsequent to, one or moreadditional therapeutically active agents. In general, each agent will beadministered at a dose and/or on a time schedule determined for thatagent. In will further be appreciated that the additionaltherapeutically active agent utilized in this combination can beadministered together in a single composition or administered separatelyin different compositions. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional therapeutically active agent and/or the desiredtherapeutic effect to be achieved. In general, it is expected thatadditional therapeutically active agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

The compounds or compositions can be administered in combination withagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that therapy employed mayachieve a desired effect for the same disorder (for example, a compoundcan be administered in combination with an anti-inflammatory,anti-anxiety and/or anti-depressive agent, etc.), and/or it may achievedifferent effects (e.g., control of adverse side-effects).

Exemplary active agents include, but are not limited to, anti-canceragents, antibiotics, anti-viral agents, anesthetics, anti-coagulants,inhibitors of an enzyme, steroidal agents, steroidal or non-steroidalanti-inflammatory agents, antihistamine, immunosuppressant agents,anti-neoplastic agents, antigens, vaccines, antibodies, decongestant,ssedatives, opioids, pain-relieving agents, analgesics, anti-pyretics,hormones, prostaglandins, progestational agents, anti-glaucoma agents,ophthalmic agents, anti-cholinergics, anti-depressants, anti-psychotics,hypnotics, tranquilizers, anti-convulsants/anti-epileptics (e.g.,Neurontin, Lyrica, valproates (e.g., Depacon), and otherneurostabilizing agents), muscle relaxants, anti-spasmodics, musclecontractants, channel blockers, miotic agents, anti-secretory agents,anti-thrombotic agents, anticoagulants, anti-cholinergics, β-adrenergicblocking agents, diuretics, cardiovascular active agents, vasoactiveagents, vasodilating agents, anti-hypertensive agents, angiogenicagents, modulators of cell-extracellular matrix interactions (e.g. cellgrowth inhibitors and anti-adhesion molecules), orinhibitors/intercalators of DNA, RNA, protein-protein interactions,protein-receptor interactions, etc. Active agents include small organicmolecules such as drug compounds (e.g., compounds approved by the Foodand Drugs Administration as provided in the Code of Federal Regulations(CFR)), peptides, proteins, carbohydrates, monosaccharides,oligosaccharides, polysaccharides, nucleoproteins, mucoproteins,lipoproteins, synthetic polypeptides or proteins, small molecules linkedto proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs,nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides,lipids, hormones, vitamins and cells.

In certain embodiments, the additional therapeutically active agent is apain-relieving agent. Exemplary pain relieving agents include, but arenot limited to, analgesics such as non-narcotic analgesics [e.g.,salicylates such as aspirin, ibuprofen (MOTRIN®, ADVIL®), ketoprofen(ORUDIS®), naproxen (NAPROSYN®), acetaminophen, indomethacin] ornarcotic analgesics [e.g., opioid analgesics such as tramadol, fentenyl,sufentanil, morphine, hydromorphone, codeine, oxycodone, andbuprenorphine]; non-steroidal anti-inflammatory agents (NSAIDs) [e.g.,aspirin, acetaminophen, COX-2 inhibitors]; steroids or anti-rheumaticagents; migraine preparations such as beta adrenergic blocking agents,ergot derivatives; tricyclic antidepressants (e.g., amitryptyline,desipramine, imipramine); anti-epileptics (e.g., clonaxepam, valproicacid, phenobarbital, phenyloin, tiagaine, gabapentin, carbamazepine,topiramate, sodium valproate); α₂ agonists; selective serotonin reuptakeinhibitors (SSRIs), selective norepinepherine uptake inhibitors;benzodiazepines; mexiletine (MEXITIL); flecamide (TAMBOCOR); NMDAreceptor antagonists [e.g., ketamine, detromethorphan, methadone]; andtopical agents [e.g., capsaicin (Zostrix), EMLA cream, lidocaine,prilocalne].

In other embodiments, the additional therapeutically active agent is ananti-inflammatory agent. Exemplary anti-inflammatory agents include, butare not limited to, aspirin; ibuprofen; ketoprofen; naproxen; etodolac(LODINE®); COX-2 inhibitors such as celecoxib (CELEBREX®), rofecoxib(VIOXX®), valdecoxib (BEXTRA®), parecoxib, etoricoxib (MK663),deracoxib,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide,darbufelone, flosulide,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),meloxicam, nimesulide,1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo-butenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, or their physiologically acceptable salts, esters orsolvates; sulindac (CLINORIL®); diclofenac (VOLTAREN®); piroxicam(FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin(DAYPRO®), indomethacin (INDOCIN®); or steroids such as PEDIAPED®prednisolone sodium phosphate oral solution, SOLU-MEDROL®methylprednisolone sodium succinate for injection, PRELONE® brandprednisolone syrup.

Further examples of anti-inflammatory agents include naproxen, which iscommercially available in the form of EC-NAPROSYN® delayed releasetablets, NAPROSYN®, ANAPROX® and ANAPROX® DS tablets and NAPROSYN®suspension from Roche Labs, CELEBREX® brand of celecoxib tablets, VIOXX®brand of rofecoxib, CELESTONE® brand of betamethasone, CUPRAMINE® brandpenicillamine capsules, DEPEN® brand titratable penicillamine tablets,DEPO-MEDROL brand of methylprednisolone acetate injectable suspension,ARAVA™ leflunomide tablets, AZULFIDIINE EN-tabs® brand of sulfasalazinedelayed release tablets, FELDENE® brand piroxicam capsules, CATAFLAM®diclofenac potassium tablets, VOLTAREN® diclofenac sodium delayedrelease tablets, VOLTAREN®-XR diclofenac sodium extended releasetablets, or ENBREL® etanerecept products.

V. Methods of Determining Biological Activity

Methods of determining the activity of the compounds provided herein forvarious therapeutic uses are known in the art. These include, but arenot limited to, high throughput screening to identify compounds thatbind to and/or modulate the activity of isolated FAAH, as well as invitro and in vivo models of therapies.

Assays useful for screening the compounds provided herein may detect thebinding of the inhibitor to FAAH or the release of a reaction product(e.g., fatty acid amide or ethanolamine) produced by the hydrolysis of asubstrate such as oleoylethanolamide or ananadamide. The substrate canbe labeled to facilitate detection of the released reaction products.U.S. Pat. No. 5,559,410 discloses high throughput screening methods forproteins, and U.S. Pat. Nos. 5,576,220 and 5,541,061 disclose highthroughput methods of screening for ligand/antibody binding.

Methods for screening FAAH inhibitors for an antinociceptive effect areknown in the art. For example, compounds can tested in the mousehot-plate test and the mouse formalin test, and the nociceptivereactions to thermal or chemical tissue damage measured (for example,see U.S. Pat. No. 6,326,156 for a description of methods of screeningfor antinociceptive activity; see also Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. (2001) 98:9371-9376).

Two pharmacologically validated animal models of anxiety are theelevated zero maze test, and the isolation-induced ultrasonic emissiontest. The zero maze consists of an elevated annular platform with twoopen and two closed quadrants and is based on the conflict between ananimal's instinct to explore its environment and its fear of open spaces(see, for example, Bickerdike, M. J. et al., Eur. J. Pharmacol., (994)271, 403-411; Shepherd, J. K. et al., Psychopharmacology, (1994) 116,56-64). Clinically used anxiolytic drugs, such as the benzodiazepines,increase the proportion of time spent in, and the number of entries madeinto, the open compartments.

A second test for an anti-anxiety compound is the ultrasonicvocalization emission model, which measures the number of stress-inducedvocalizations emitted by rat pups removed from their nest (see, forexample, Insel, T. R. et al., Pharmacol. Biochem. Behav., 24, 1263-1267(1986); Miczek, K. A. et al., Psychopharmacology, 121, 38-56 (1995);Winslow, J. T. et al., Biol. Psychiatry, 15, 745-757 (1991).

The effect of the compounds provided herein in the treatment ofdepression can be tested in the model of chronic mild stress inducedanhedonia in rats. This model is based on the observation that chronicmild stress causes a gradual decrease in sensitivity to rewards, forexample consumption of sucrose, and that this decrease isdose-dependently reversed by chronic treatment with antidepressants.See, e.g., Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

Another test for antidepressant activity is the forced swimming test(Nature 266, 730-732, 1977). In this test, animals are administered anagent 30 or 60 minutes before being placed in container of water, andthe time during which they remain immobile is recorded. A decrease inthe immobility time of the mice is indicative of antidepressantactivity.

A similar test for antidepressant activity is the mouse caudalsuspension test (Psychopharmacology, 85, 367-370, 1985). In this test,animals are administered an agent 30 or 60 minutes before beingsuspended by the tail, and their immobility time is recorded. A decreasein the immobility time of the mice is indicative of antidepressantactivity.

Animal models are available for assessing anticonvulsant activity oftest compounds (see, e.g., U.S. Pat. Nos. 6,309,406 and 6,326,156).

Inhibition of FAAH has been reported to induce sleep in test animals(see, e.g., U.S. Pat. No. 6,096,784). Methods for studying sleepinducing compounds are known in the art (see, e.g., U.S. Pat. Nos.6,096,784 and 6,271,015). Compounds can be administered to a test animal(e.g., rat or mouse) or a human and the subsequent time (e.g., onset,duration) spent sleeping (e.g., eyes closed, motor quiescence) can bemonitored. See also WO 98/24396.

Methods for screening FAAH inhibitors which induce catalepsy are alsowell known in the art (see, e.g., Quistand et al. in Toxicology andApplied Pharmacology 173: 48-55 (2001); Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. 98:9371-9376 (2001)).

Methods of assessing appetitive behavior are known in the art (see,e.g., U.S. Pat. No. 6,344,474). One method of assessing the effect onappetite behavior is to administer a FAAH inhibitor to a rat and assessits effect on the intake of a sucrose solution (see, e.g., W. C. Lynchet al., Physiol. Behav., 1993, 54, 877-880).

Two pharmacologically validated animal models of neuropathic pain arethe rat spinal nerve ligation model (Chung model) and a rat model ofchemotherapy-induced neuropathic pain. After establishing neuropathy inthese models, as a measure of mechanical allodynia, paw withdrawalthresholds were measured by stimulation with von Frey filaments (see,for example, Kim S H and Chung J M, Pain (1992) 50, 355-63;Nozaki-Taguchi N, et al., Pain (2001) 93, 69-76). Clinically usedneuropathic pain drugs, such as the Gabapentin (Neurontin), increase thepaw withdrawal threshold from stimulation with von Frey filaments.

Two pharmacologically validated animal models of inflammatory andmechanical pain are a joint compression model in rats treated withadjuvant or agents that produce joint degeneration. Treatment withclinically used anti-inflammatory agents such as naproxen increases thethreshold of behavioral response to joint compression (see, for example,Wilson A W, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius S A, etal., Pain (2007) 128, 272-282).

A pharmacologically validated animal models of cancer pain is mousemodel where implantation in the calcaneus bone of fibrosarcoma cellsproduces paw hyperalgesia. Treatment with clinically used analgesicsagents such as morphine increases the threshold of behavioral responseto mechanical algesia (see, for example, Khasabova, et al., J.Neurscience (2008) 28, 11141-52).

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

General Synthetic Methods Method 1

General conditions for the preparation of 3-bromo-isoxazolines: Alkene(1.2 equiv) and potassium hydrogen carbonate (2.5 equiv) are suspendedin ethyl acetate (0.40 M with respect to alkene).N,N-Dibromoformaldoxime (1.0 equiv) is added and the reaction wasallowed to stir at 23° C. for 14-28 h. Upon completion as judged by thinlayer chromatography analysis, the reaction was split between water andtert-butyl methyl ether, and the organic layer was washed with water andbrine, dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-bromo-isoxazoline.

Method 2

General conditions for the preparation of 3-bromo-isoxazolines: A flaskis charged with glyoxylic acid monohydrate (1.0 equiv) and hydroxylaminehydrochloride (1.1 equiv). The mixture was dissolved in water (2.0 Mwith respect to glyoxylic acid monohydrate) and stirred at 23° C. for 24h. The mixture was diluted with water and extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated toprovide the desired crude oxime which was used directly in subsequentcycloaddition. The resulting oxime (1.1 equiv) from the first step issuspended in a 3:1 mixture of dimethoxyethane:water (v/v) (0.15 M withrespect to oxime) and cooled to 0° C. N-Bromosuccinamide (NBS) (2.0equiv) was added and the reaction was allowed to stir at 23° C. for 20min. The resulting mixture is then added to a solution of alkene (1.0equiv) and potassium bicarbonate (2.5 equiv) in dimethoxyethane (1.50 Mwith respect to alkene) and the reaction is allowed to stir for 20 h at23° C. Upon completion as judged by thin layer chromatography analysis,the reaction was split between water and tert-butyl methyl ether, andthe organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The concentrated reaction mixture was purified byflash silica gel chromatography (ethyl acetate/hexanes) to provide thedesired 3-bromo-isoxazoline.

Method 3

General conditions for the preparation of 3-aryloxy-isoxazolines or3-heteroaryloxy-isoxazolines: A microwave reaction vial is charged witha given 3-bromo-isoxazoline (1.0 equiv) and an alcohol (e.g., a phenolor a hydroxypyridine) (3.0 equiv) and dissolved in N-methylpyrrolidine(0.50 M with respect to isoxazoline). Crushed sodium hydroxide (2.0equiv) is added and the mixture was sealed and heated in a microwavereaction at 150° C. for 30 min. The reaction was then split betweenwater and tert-butyl methyl ether, and the organic layer was washed withbrine, dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desiredisoxazoline.

Method 4

General conditions for the preparation of 3-aryloxy-isoxazolines or3-heteroaryloxy-isoxazolines: A flask is charged with a given3-bromo-isoxazoline (1.0 equiv) and the alcohol (e.g., a phenol or ahydroxypyridine) (2.0 equiv) and dissolved in N,N-dimethylforamide (0.4M with respect to isoxazoline). Sodium hydride (2.0 equiv) is added andthe reaction is allowed to stir for 10 min until all of the gasevolution ceases. The reaction is then heated to 150° C. for 1-5 h.After the reaction is determine to be complete by thin layerchromatography analysis, the reaction was then split between water andethyl acetate, and the organic layer was washed with 1N NaOH and brine,and then dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desiredisoxazoline.

Method 5

General conditions for the preparation of 3-aryloxy-isoxazolines: Aflask is charged with a given 3-bromo-isoxazoline (1.0 equiv) and thealcohol (e.g., a phenol or a hydroxypyridine) (2.0 equiv) and dissolvedin N,N-dimethylforamide or N-methylpyrrolidinone (0.15 M with respect toisoxazole). Cesium carbonate (1.2 to 3 equiv) is added and the reactionis heated to 120° C. in an oil bath for 1 h. The reaction was then splitbetween water and tert-butyl methyl ether, and the organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The concentrated reaction mixture was purified by flash silica gelchromatography (methanol/methylene chloride) to provide the desiredisoxazoline.

Method 6

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.25 M methyltriphenylphosphonium bromide (1.1 equiv)dissolved in tetrahydrofuran was cooled to 0° C. after which the mixturewas treated drop wise with sodium hexamethyldisilazane (NaHMDS) intetrahydrofuran (1.0 M, 1.2 equiv). After stirring an additional 30 minat 0° C., a given aldehyde or ketone is added and the reaction isallowed to warm slowly to 23° C. overnight. The mixture was quenchedsaturated ammonium chloride and concentrated to remove thetetrahydrofuran. The mixture was then diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and concentrated in vacuo. The concentrated reactionmixture was purified by flash silica gel chromatography (ethylacetate/hexanes) to provide the desired alkene.

Method 7

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.15 M methyltriphenylphosphonium bromide (1.5 equiv)dissolved in tetrahydrofuran was cooled to −78° C. after which themixture was treated drop wise with n-butyl lithium in hexanes (2.5 M,1.5 equiv). After stirring an additional 1 h at −78° C., a givenaldehyde or ketone is added and the reaction is allowed to warm slowlyto 23° C. overnight. The mixture was quenched saturated ammoniumchloride and concentrated to remove the tetrahydrofuran. The mixture wasthen diluted with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate and concentratedin vacuo. The concentrated reaction mixture was purified by flash silicagel chromatography (ethyl acetate/hexanes) to provide the desiredalkene.

Method 8

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.12 M methyltriphenylphosphonium bromide (2.5 equiv) wasdissolved in tetrahydrofuran after which potassium tert-butoxide (4.0equiv) was added in six portions. After stirring an additional 1 h at23° C., a given aldehyde or ketone is added and the reaction was heatedto 55° C. for 2 h. The mixture was quenched saturated ammonium chlorideand concentrated to remove the tetrahydrofuran. The mixture was thenacidified to pH 5-6 with 1N HCl and extracted with methylene chloride.The organic layer was washed with brine and then dried over sodiumsulfate and concentrated in vacuo. The concentrated reaction mixture waspurified by flash silica gel chromatography (ethyl acetate/hexanes) toprovide the desired alkene.

Method 9

General conditions for the preparation of styrenes: a dry flask underargon atmosphere was charged with aryl bromide (1.0 equiv), potassiumvinyltrifluoroborate (1.2 equiv),1,1″-bis(diphenylphosphino)-ferrocenedichloropalladium(II) methylenechloride adduct (0.02 equiv) and triethylamine (1.0 equiv) and themixture was suspended in isopropanol (0.25 M with respect to arylbromide) and heated at 80° C. for 2-24 h. The mixture was then dilutedwith water and extracted with diethyl ether. The organic layer waswashed with brine and then dried over magnesium sulfate and concentratedin vacuo. The concentrated reaction mixture was purified by flash silicagel chromatography (ethyl acetate/hexanes) to provide the desiredstyrene.

Method 10

General conditions for the preparation of styrenes: a dry flask under anitrogen atmosphere was charged with aryl bromide (1.0 equiv),tributylvinyltin (1.1 equiv) and dissolved in toluene (0.3 M withrespect to bromide). The resulting mixture was further purged withnitrogen for 10 min after which tetrakis(triphenyphosphine)palladium(0.1 equiv) was added and the reaction was refluxed for 1.5 h. After thereaction was determined to be complete by TLC analysis, it was allowedto cool and loaded directly onto a silica gel column where it waspurified by flash silica gel chromatography (ethyl acetate/hexanes) toprovide the desired styrene.

Method 11

General conditions for the hydrolysis of pyridyl and pyrimidinyl boronicacids to their corresponding phenols: A flask is charged with a givenboronic acid or ester thereof (1.0 equiv) and dissolved intetrahydrofuran (1.1 M, 10 volumes). Sodium perborate (1.0 equiv) isdissolved in water (1.1 M with respect to boronic acid, 10 volumes) andsonicated for 10 min. The perborate suspension is then added to the THFsolution using tetrahydrofuran (1.6 volumes) to rinse the remainingsolid perborate into the reaction mixture. The reaction is allowed tostir at room temperature (reaction is mildly exothermic) after whichammonium chloride is added in three portions (10 equiv) and the reactioncooled back down to room temperature. After 40 min, the reaction wasconcentrated under vacuum until all of the tetrahydrofuran was removed.The resulting solid was collected by vacuum filtration, washed withexcess waster and dried in a vacuum oven for 40° C. for 3d to providethe desired phenol in 80% yield.

Chiral HPLC Method

Enantiomeric or diastereomeric mixtures of compounds can be separatedusing known methods, including chiral high pressure liquidchromatography (HPLC) and chiral supercritical fluid chromatography(SFC). Exemplary chiral columns found useful in separating such mixturesof compounds of the present invention include, but are not limited to,ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack™, and S,SWhelkO®-1 and LUX™ Cellulose2 columns. One or more of these columns wereused to separate enantiomeric mixtures of compounds of the presentinvention in order to obtain substantially enantiomerically purecompounds.

Synthesis of Exemplary Compounds of Formula I

Syntheses of exemplary compounds are set forth below. Compounds wereassayed as inhibitors of human FAAH using the method described in detailin Example 254. Activity designated as “A” refers to compounds having aK_(i) of less than or equal to 100 nM, “B” refers to compounds having aK_(i) of between 100 nM and 1 microM, and “C” refers to compounds havinga K_(i) of greater than or equal to 1 microM.

Example 1

3-bromo-4,5-dihydroisoxazole I-1a and I-1b were prepared in 1 step fromstyrene using Method 2. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M−H]−=225.0 m/z. Activity: B

Example 2

3-bromo-4,5-dihydroisoxazole I-2a and I-2b were prepared in 1 step from4-fluorostyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. Activity: B

Example 3

3-bromo-4,5-dihydroisoxazole I-3a and I-3b were prepared in 1 step from4-chlorostyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=259.0 m/z. Activity: A

Example 4

3-bromo-4,5-dihydroisoxazole I-4a and I-4-b were prepared in 1 step from3-chlorostyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=258.9 m/z. Activity: B

Example 5

3-bromo-4,5-dihydroisoxazole I-5a and I-5b were prepared in 1 step from2-chlorostyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=258.9 m/z. Activity: B

Example 6

3-bromo-4,5-dihydroisoxazole I-6a and I-6b were prepared in 1 step from4-methoxystyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=255.0 m/z. Activity: A

Example 7

3-bromo-4,5-dihydroisoxazole I-7a and I-7b were prepared in 1 step from3-methoxystyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=255.0 m/z. Activity: B

Example 8

3-bromo-4,5-dihydroisoxazole I-8a and I-8b were prepared in 1 step from2-methoxystyrene using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=255.0 m/z. Activity: C

Example 9

-   -   (I-9)

3-bromo-4,5-dihydroisoxazole I-9a and I-9b were prepared in 1 step from4-vinylbiphenyl using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=301.6 m/z. Activity: A

Example 10

3-bromo-4,5-dihydroisoxazole I-10a and I-10b were prepared in 1 stepfrom 4-phenoxystyrene using Method 2. These compounds were separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=317.0 m/z. Activity: A

Example 11

3-bromo-4,5-dihydroisoxazole I-11a and I-11b were prepared in 2 stepsstarting with alkene formation from 3-phenoxybenzaldehyde using Method 8followed by cycloaddition using Method 2. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]=317.0 m/z. Activity: A

Example 12

3-bromo-4,5-dihydroisoxazole I-12a and I-12b were prepared in 2 stepsstarting with alkene formation from 4-(pyridin-3-yloxy)benzaldehydeusing Method 8 followed by cycloaddition using Method 2. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]=318.0 m/z.Activity: A

Example 13

3-bromo-4,5-dihydroisoxazole I-13a and I-13b were prepared in 2 stepsstarting with alkene formation from 4-(pyrimidin-2-yloxy)-benzaldehydeusing Method 8 followed by cycloaddition using Method 2. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=319.0 m/z.Activity: A

Example 14

3-bromo-4,5-dihydroisoxazole I-14a and I-14b were prepared in 2 stepsstarting with alkene formation from 4-trifluoromethoxybenzaldehyde usingMethod 8 followed by cycloaddition using Method 1. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=309.6 m/z. Activity: A

Example 15

3-bromo-4,5-dihydroisoxazole I-15a and I-15b were prepared in 2 stepsstarting with alkene formation from 4-isopropoxybenzaldehyde usingMethod 8 followed by cycloaddition using Method 2. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M−H]−=238.0 m/z. Activity: A

Example 16

3-bromo-4,5-dihydroisoxazole I-16a and I-16b were prepared in 2 stepsstarting with alkene formation from piperonal using Method 7 followed bycycloaddition using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=269.0 m/z. Activity: A

Example 17

3-chloro-4,5-dihydroisoxazole I-17a and I-17b were prepared in using theanalogous procedure as Example 10 except that N-chlorosuccinamide wasused in the place of N-bromosuccinamide. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=273.1 m/z. Activity: A

Example 18

3-bromo-4,5-dihydroisoxazole I-18a and I-18b were prepared in 2 stepsstarting with alkene formation from3-(4-bromophenoxy)-6-methylpyridazine using Method 9 followed bycycloaddition using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=333.0 m/z. Activity: B

Example 19

3-bromo-4,5-dihydroisoxazole I-19a and I-19b were prepared in 2 stepsstarting with alkene formation from2-(4-bromophenyl)-5-phenyl-1,3,4-oxadiazole using Method 9 followed bycycloaddition using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=369.0 m/z. Activity: A

Example 20

3-bromo-4,5-dihydroisoxazole I-20a and I-20b were prepared in 2 stepsstarting with alkene formation from 4-butoxybenzaldehyde using Method 8followed by cycloaddition using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=297.0 m/z. Activity: A

Example 21

3-bromo-4,5-dihydroisoxazole I-21a and I-21b were prepared in 2 stepsstarting with the coupling between 4-vinylbenzoic acid and benzylalcohol as follows: 4-Vinylbenzoic acid (1.0 equiv) is dissolved inN,N-dimethylforamide (0.20 M with respect to acid). Benzyl alcohol isadded (2.0 equiv) followed by EDC (1.05 equiv) and a catalytic amount ofDMAP (0.05 equiv). The reaction is allowed to stir at 23° C. for 14 hafter which point the reaction was split between water and tert-butylmethyl ether, and the organic layer was washed with 0.5 M citric acidsolution (2×) and saturated sodium bicarbonate solution (1×), dried overmagnesium sulfate, and concentrated in vacuo. The concentrated reactionmixture was purified by flash silica gel chromatography (ethylacetate/hexanes) to provide the desired ester. This compound was thenconverted to the desired 3-bromo-4,5-dihydroisoxazole using Method 1.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=359.8m/z. Activity: A

Example 22

3-bromo-4,5-dihydroisoxazole I-22a and I-22b were prepared in using theanalogous procedure as Example 21 except that benzylamine was used inthe place of benzyl alcohol. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=358.9 m/z. Activity: B

Example 23

3-phenoxy-4,5-dihydroisoxazole I-23a and I-23b were prepared in 1 stepfrom compound I-10 and phenol using Method 3. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=331.1 m/z. Activity: C

Example 24

3-phenoxy-4,5-dihydroisoxazole I-24a and I-24b were prepared in 1 stepfrom compound I-10 and 4-fluorophenol using Method 4. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=350.3 m/z.Activity: C

Example 25

3-phenoxy-4,5-dihydroisoxazole I-25a and I-25b were prepared in 1 stepfrom compound I-10 and 3-fluorophenol using Method 4. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=349.3 m/z.Activity: B

Example 26

3-phenoxy-4,5-dihydroisoxazole I-26a and I-26b were prepared in 1 stepfrom compound I-10 and 3-trifluoromethylphenol using Method 4. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=400.3 m/z.Activity: C

Example 27

3-phenoxy-4,5-dihydroisoxazole I-27a and I-27b were prepared in 1 stepfrom compound I-10 and 4-cyanophenol using Method 3. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M−H]−=356.1 m/z. Activity: A

Example 28

3-phenoxy-4,5-dihydroisoxazole I-28a and I-28b were prepared in 1 stepfrom compound I-10 and 2-cyanophenol using Method 4. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=357.3 m/z. Activity: C

Example 29

3-phenoxy-4,5-dihydroisoxazole I-29a and I-29b were prepared in 1 stepfrom compound I-10 and 4-nitrolphenol using Method 4. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=376.8 m/z.Activity: B

Example 30

3-phenoxy-4,5-dihydroisoxazole I-30a and I-30b were prepared in 1 stepfrom compound I-10 and 4-methylsulfonylphenol using Method 4. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=409.0 m/z.Activity: A

Example 31

3-phenoxy-4,5-dihydroisoxazole I-31a and I-31b were prepared in 1 stepfrom compound I-10 and 4-methyl-3-fluorophenol using Method 4. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=364.4 m/z.Activity: C

Example 32

A microwave reaction vial is charged with racemic compound I-10 (1.0equiv) and aniline (4.0 equiv). The mixture was sealed and heated in amicrowave reactor at 150° C. for 2 h. The reaction was then splitbetween water and tert-butyl methyl ether, and the organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The concentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-amino-4,5-dihydroisoxazole I-32a and I-32b. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=330.1 m/z. Activity: C.

Example 33

1-(4,5-dihydroisoxazol-3-yl)pyridin-2(1H)-one I-33a and I-33b wereprepared in 1 step from racemic compound I-10 and 2-hydroxypyridineusing Method 3. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=332.1 m/z. Activity: C

Example 34

A microwave reaction vial is charged with racemic ompound I-10 (1.0equiv) and the sodium salt of 1,2,4-triazole (2.0 equiv). The reagentsare dissolved in N-methylpyrrolidine (0.18 M with respect to compoundI-10). The mixture was sealed and heated in a microwave reactor at 100°C. for 30 min. Excess water is added and a brown solid crashes out whichis isolated using vacuum filtration and dried to provide the desired3-(1H-1,2,4-triazol-1-yl)-4,5-dihydroisoxazole I-34a and I-34b. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=306.1 m/z.Activity: C.

Example 35

Pyrazole (3.0 equiv) was dissolved in N,N-dimethylforamide (0.60 M withrespect to pyraole) and NaH (60% dispersion in mineral oil, 3.0 equiv)was added and the reaction was allowed to stir under nitrogen for 5 min.After that point racemic compound I-10 was added. The reaction was thenheated to 90° C. for 14 h after which it was cooled and quenched withmethanol (0.30 M with prespect to pyrazole). The crude mixture wasfiltered through cotton and directly purified by semi-prep reverse phasechromatograpy to provide the desired3-(1H-pyrazol-1-yl)-4,5-dihydroisoxazole I-35a and I-35b. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=306.4 m/z.Activity: C.

Example 36

3-(pyridin-4-yloxy)-4,5-dihydroisoxazole I-36a and I-36b were preparedin 1 step from compound I-10 and 4-hydroxypyridine using Method 3. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=332.1 m/z.Activity: C

Example 37

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-37a and I-37b were preparedin 1 step from racemic compound I-10 and 3-hydroxypyridine using Method3 or Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=332.1 m/z. Activity: A

Example 38

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-38a and I-38b were preparedin 1 step from racemic compound I-6 and 3-hydroxypyridine using Method3. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M−H]−=270.1 m/z. Activity: B

Example 39

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-39a and I-39b were preparedin 1 step from racemic compound I-10 and methyl 5-hydroxynicotinateusing Method 3 or Method 5. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=392.2 m/z. Activity: A

Example 40

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-40a and I-40b were preparedin 1 step from racemic compound I-10 and 5-hydroxy-2-methylpyridineusing Method 4. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=346.1 m/z. Activity: A

Example 41

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-41a and I-41b were preparedin 1 step from racemic compound I-10 and 5-hydroxypyrimidine usingMethod 3. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M−H]−=333.1 m/z. Activity: A

Example 42

3-(quinolin-3-yloxy)-4,5-dihydroisoxazole I-42a and I-42b were preparedin 1 step from racemic compound I-10 and 3-hydroxyquinoline using Method3. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M−H]−=382.1 m/z. Activity: A

Example 43

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-43a and I-43b was prepared in1 step from racemic compound I-10 and 5-fluoro-3-hydroxypyridine usingMethod 3. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M−H]−=350.1 m/z. Activity: A

Example 44

3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4,5-dihydroisoxazole I-4aand I-44b were prepared in 1 step from racemic compound I-10 and1-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol using Method 3. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=385.1 m/z.Activity: B

Example 45

A vial is charged with racemic compound I-10 (1.0 equiv) and dissolvedin methanol (0.05 M with respect to isoxazole). Potassium carbonate (5.0equiv) was added and the reaction was sealed and heated to 50° C. for 24h. The reaction was then split between water and ethyl acetate, and theorganic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The concentrated reaction mixture was purified byflash silica gel chromatography (ethyl acetate/hexanes) to provide thedesired 3-methoxy-4,5-dihydroisoxazole I-45a and I-45b. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=269.1 m/z.Activity: C.

Example 46

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-46a and I-46b were preparedin 1 step from racemic compound I-14 and methyl 5-hydroxynicotinateusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=384.0 m/z. Activity: B

Example 47

Racemic compound I-39 is dissolved in ammonia in methanol (7.0 M inmethanol, 0.02 M with respect to isoxazole). The reaction is sealed andallowed to stir at 23° C. for 24 h after which point the solvent andexcess ammonia are removed under a stream of nitrogen to provide a lightbrown solid which is triturated with hexanes to provide the desiredamide I-47a and I-47b as a white solid. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=374.0 m/z. Activity: B

Example 48

3-bromo-4,5-dihydroisoxazole I-48a and I-48b were prepared in 1 stepfrom 3-phenyl-1-propene using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=239.0 m/z. Activity: C

Example 49

3-bromo-4,5-dihydroisoxazole I-49a and I-49b were prepared in 1 stepfrom 4-phenyl-1-butene using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=253.0 m/z. Activity: B

Example 50

Phenol (1.0 equiv) is dissolved in ethanol (0.5 M with respect tophenol) and sodium hydroxide (1.0 equiv) is added followed by theaddition of 4-bromo-1-butene. The mixture is heated to reflux for 1 hafter which the majority of the solvent is removed under vacuum. Thereaction was then split between water and tert-butyl methyl ether, andthe organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo to provide crude alkene which was directlyconverted to the desired 3-bromo-4,5-dihydroisoxazole I-50a and I-50b in1 step using Method 2. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M−H]−=269.0 m/z. Activity: B

Example 51

Phenol (1.2 equiv) is dissolved in N,N-dimethylforamide (0.4 M withrespect to phenol) and cesium carbonate (1.3 equiv) is added followed bythe addition of 5-bromo-1-pentene (1.0 equiv) and tetrabutylammoniumiodide (0.10 equiv). The mixture is heated to 50° C. for 16 h. Thereaction was then split between water and tert-butyl methyl ether, andthe organic layer was washed with dilute sodium hydroxide solution,water, brine, dried over sodium sulfate, and concentrated in vacuo. Thecrude alkene was directly converted to the desired3-bromo-4,5-dihydroisoxazole I-51a and I-51b in 1 step using Method 2.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M−H]−=283.0m/z. Activity: A

Example 52

2-Phenylethanol (1.0 equiv) is dissolved in N,N-dimethylforamide (0.8 Mwith respect to alcohol) and crushed sodium hydroxide (2.0 equiv) isadded followed by the addition of allyl bromide (1.0 equiv) andtetrabutylammonium iodide (0.10 equiv). The mixture is stirred at roomtemperature for 48 h. The reaction was then split between water andtert-butylmethyl ether, and the organic layer was washed with diluteNa₂S₂O₃ solution and brine, dried over sodium sulfate, and concentratedin vacuo. The concentrated reaction mixture was purified by flash silicagel chromatography (ethyl acetate/hexanes) to provide the desired alkenewhich was directly converted to the desired 3-bromo-4,5-dihydroisoxazoleI-52a and I-52b in 1 step using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=285.6 m/z. Activity: B

Example 53

Racemic compound I-46 is dissolved in ammonia in methanol (7.0 M inmethanol, 0.02 M with respect to isoxazole). The reaction is sealed andallowed to stir at 23° C. for 72 h after which point the solvent andexcess ammonia are removed under a stream of nitrogen to provide a lightbrown solid which is triturated with hexanes to provide desired amideI-53a and I-53b as a white solid. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=366.0 m/z. Activity: B

Example 54

Racemic compound I-46 is dissolved in ammonia in methylamine (2.0 M intetrahydrofuran, 0.02 M with respect to isoxazole). The reaction issealed and allowed to stir at 23° C. for 72 h after which point thesolvent and excess ammonia are removed under a stream of nitrogen toprovide a light brown solid which is triturated with hexanes to providedesired amide I-54a and I-54b as a white solid. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=380.0 m/z. Activity: A

Example 55

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-55a and I-55b were preparedin 1 step from racemic compound I-46 and methyl 5-hydroxynicotinateusing Method 5 and was isolated as a side product from the reactionduring flash silica gel chromatography. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=367.0 m/z. Activity: C

Example 56

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-56a and I-56b was prepared in1 step from racemic compound I-10 and5-hydroxy-2-trifluoromethylpyridine using Method 5. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=401.5 m/z. Activity: A

Example 57

3-(1H-pyrrolo[3,2-b]pyridin-6-yloxy)-4,5-dihydroisoxazole I-57a andI-57b were prepared in 1 step from racemic compound I-10 and1H-pyrrolo[3,2-b]pyridin-6-ol using Method 5. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=370.0 m/z. Activity: A

Example 58

3-phenoxy-4,5-dihydroisoxazole I-58a and I-58b were prepared in 1 stepfrom racemic compound I-10 and 3-cyanophenol using Method 4. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=356.8 m/z.Activity: B

Example 59

3-phenoxy-4,5-dihydroisoxazole I-59a and I-59b were prepared in 1 stepfrom racemic compound I-10 and 2-fluorophenol using Method 4. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=350.3 m/z.Activity: B

Example 60

3-phenoxy-4,5-dihydroisoxazole I-60a and I-60b were prepared in 1 stepfrom racemic compound I-10 and 4-fluoro-3-(trifluoromethyl)phenol usingMethod 4. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.Activity: C

Example 61

3-phenoxy-4,5-dihydroisoxazole I-61a and I-61b were prepared in 1 stepfrom racemic compound I-10 and methyl 3-hydroxybenzoate using Method 4.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=390.5m/z. Activity: A

Example 62

3-phenoxy-4,5-dihydroisoxazole I-62a and I-62b were prepared in 1 stepfrom racemic compound I-10 and methyl 4-hydroxybenzoate using Method 4.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=389.7m/z. Activity: A

Example 63

3-phenoxy-4,5-dihydroisoxazole I-63a and I-63b were prepared in 1 stepfrom racemic compound I-10 and 3-(methylsulfonyl)phenol using Method 4.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M−H]−=409.0m/z. Activity: C

Example 64

3-phenoxy-4,5-dihydroisoxazole I-64a and I-64b were prepared in 1 stepfrom racemic compound I-10 and 3-hydroxybenzenesulfonamide using Method4. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M−H]−=409.0 m/z. Activity: C

Example 65

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-65a and I-65b were preparedin 1 step from racemic compound I-10 and 5-methoxypyridin-3-ol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=363.2 m/z. Activity: A

Example 66

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-66a and I-66b were preparedin 1 step from racemic compound I-10 and 5-hydroxypyrimidine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=364.6 m/z. Activity: A

Example 67

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-67a and I-67b were preparedin 1 step from racemic compound I-10 and methyl 5-hydroxypicolinateusing Method 3. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=392.1 m/z. Activity: A

Example 68

3-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4,5-dihydroisoxazole I-68a andI-68b were prepared in 1 step from racemic compound I-10 and1H-pyrrolo[2,3-b]pyridin-5-ol using Method 5. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=370.0 m/z. Activity: A

Example 69

6-(4,5-dihydroisoxazol-3-yloxy)furo[3,2-b]pyridine I-69a and I-69b wereprepared in 2 steps from racemic compound I-10 andfuro[3,2-b]pyridin-6-ol using Method 5 after furo[3,2-b]pyridin-6-ol isprepared from6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridine usingMethod 11. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=374.2 m/z. Activity: A

Example 70

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-70a and I-70b were preparedin 1 step from racemic compound I-14 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=324.1 m/z. Activity: A

Example 71

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-71a and I-71b were preparedin 1 step from racemic compound I-14 and 5-bromo-3-hydroxypyridine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=402.5 m/z. Activity: A

Example 72

Racemic compound I-71 (1.0 equiv), phenyl boronic acid (1.1 equiv),potassium acetate (1.0 equiv), cesium carbonate (3.0 equiv), anddichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II)dichloromethane adduct (14 mol %) were suspended in 1 mL DMSO andpurgetd with Ar. The resulting mixture was sealed and heated to 80° C.for 1 h. The crude mixture was transferred to a separatory funnel withexcess water and extracted with methyl tert-butylether (2×). The organiclayers were combined, dried over Na₂SO₄ and purified using flash silicagel chromatography (gradient of 2-10% MeOH) to provided the desired3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-72a and I-72b as a whitesolid. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=402.3 m/z. Activity: B

Example 73

Racemic compound I-71 (1.0 equiv), 3-carbamoylphenyl boronic acid (1.1equiv), potassium acetate (1.0 equiv), cesium carbonate (3.0 equiv), anddichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II)dichloromethane adduct (14 mol %) were suspended in 1 mL DMSO and purgedwith Ar. The resulting mixture was sealed and heated to 80° C. for 1 h.The crude mixture was transferred to a separatory funnel with excesswater and extracted with methyl tert-butylether (2×). The organic layerswere combined, dried over Na₂SO₄ and purified using flash silica gelchromatography (gradient of 2-10% MeOH) to provided the desired3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-73a and I-73b as a whitesolid. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M−H]−=442.0 m/z. Activity: A

Example 74

3-bromo-4,5-dihydroisoxazole I-74a and I-74b were prepared in 1 stepfrom methyl 4-vinylbenzoate using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=283.6 m/z. Activity: A

Example 75

3-bromo-4,5-dihydroisoxazole I-75a and I-75b were prepared in 2 stepsstarting with alkene formation from 4′(trifluoromethoxy)acetophenoneusing Method 6 followed by cycloaddition using Method 1. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=323.0 m/z.Activity: A

Example 76

3-bromo-4,5-dihydroisoxazole I-76a and I-76b were prepared in 2 stepsstarting with alkene formation from 4′-phenoxyacetophenone using Method6 followed by cycloaddition using Method 2. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=331.0 m/z. Activity: A

Example 77

3-bromo-4,5-dihydroisoxazole I-77a and I-77b were prepared in 1 stepfrom trans-anethole using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=269.0 m/z. Activity: C

Example 78

3-bromo-4,5-dihydroisoxazole I-78a and I-78b were was prepared in 2steps starting with alkene formation from 4-phenoxybenzaldehyde usingMethod 6 (except that ethyltriphenyphosphonium bromide is used in theplace of methyltriphenylphosphoium bromide) followed by cycloadditionusing Method 2. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=331.0 m/z. Activity: A

Example 79

3-bromo-4,5-dihydroisoxazole I-82a and I-82b were prepared in 3 stepsfrom 4-phenoxybenzaldehyde as follows: 4-Phenoxybenzaldehyde (1.0 equiv)is dissolved in tetrahydrofuran (0.20 M with respect to tetrahydrofuran)and cooled to 0° C. Ethyl magnesium bromide (1.0 M in THF, 1.2 equiv) isadded dropwise after which the reaction is allowed to stir at 23° C. for2 h. The mixture was quenched with saturated ammonium chloride andconcentrated to remove the tetrahydrofuran. The mixture was then dilutedwith water and extracted with tert-butyl methyl ether. The organic layerwas washed with water and brine and then dried over sodium sulfate andconcentrated in vacuo. The concentrated reaction mixture was purified byflash silica gel chromatography (ethyl acetate/hexanes) to provide thedesired alcohol I-80.

The purified alcohol I-80 is then dissolved in pyridine (0.80 M withrespect to alcohol). Phosphorus oxychloride (1.1 equiv) is added and themixture was heated to reflux for 2 h. After this point the reaction iscooled to 0° C. and quenched with the addition of excess water. Themixture was then diluted with ethyl acetate. The organic layer waswashed with water and brine and then dried over sodium sulfate andconcentrated in vacuo. The concentrated reaction mixture was purified byflash silica gel chromatography (ethyl acetate/hexanes) to provide thedesired alkene I-81.

Alkene I-81 was then converted to the desired3-bromo-4,5-dihydroisoxazole I-82a and I-82b using Method 2. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=331.0 m/z.Activity: B.

Example 80

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-83a and I-83b were preparedin 1 step from racemic compound I-14 and methyl3-(5-hydroxypyridin-2-yl)benzoate using Method 5. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=460.1 m/z. Activity: B

Example 81

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-84a and I-84b were preparedin 1 step from racemic compound I-14 and ethyl3-(5-hydroxypyridin-2-yl)benzoate using Method 5. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=474.1 m/z. Activity: B

Example 82

Racemic compound I-83 (1.0 equiv) was dissolved in 1:1tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) wasadded. The reaction was allowed to stir at room temperature for 1 hafter which point the tetrahydrofuran was removed under a stream ofnitrogen and the remaining solution was acidified to pH<2 with 1N HCl toprovide the desired acid I-85a and I-85b as a white solid which wasisolated via vacuum filtration. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=443.0 m/z. Activity: B

Example 83

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-86a and I-86b were preparedin 1 step from racemic compound I-14 and 6-phenylpyridin-3-ol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=402.2 m/z. Activity: B

Example 84

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-87a and I-87b were preparedin 1 step from racemic compound I-12 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=333.5 m/z. Activity: A

Example 85

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-88a and I-88b were preparedin 1 step from racemic compound I-75 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=340.2 m/z. Activity: B

Example 86

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-89a and I-89b were preparedin 1 step from racemic compound I-76 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=348.4 m/z. Activity: A

Example 87

3-phenoxy-4,5-dihydroisoxazole I-90a and I-90b were prepared in 1 stepfrom racemic compound I-10 and 4-hydroxybenzenesulfonamide using Method4. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=410.8 m/z. Activity: A

Example 88

The trans 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-91a and I-91b wereprepared in 1 step from either racemic compound I-78 or I-82 and3-hydroxypyridine using Method 5. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=346.2 m/z. Activity: C

Example 89

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-92a and I-92b were preparedin 2 steps from racemic compound I-10 and(5-hydroxy-pyridin-2-yl)-carbamic acid tert-butyl ester using Method 5after formation of (5-hydroxy-pyridin-2-yl)-carbamic acid tert-butylester from tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamateusing Method 11. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=447.9 m/z. Activity: C

Example 90

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-92 was dissolved intrifluoroacetic acid (0.20 M with respect to isoxazole) and stirred atroom temperature for 1 h. The solvent is then removed under vacuum andthe crude residue is azeotroped with toluene (2×) to provide I-93a andI-93b as the TFA salt (white solid). These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=347.1 m/z. Activity: A

Example 91

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-93 was dissolved inmethylene chloride (0.03 M with respect to isxozaole) after whichtriethylamine (4.0 equiv) and acetic anhydride (3.0 equiv are added).The reaction is allowed to stir for 16 h after which point is dilutedwith ethyl acetate and washed with saturated NaHCO₃ (2×) and brine (1×).The organic layer is then dried over sodium sulfate and concentratedunder vacuum to provide acetate I-94a and I-94b as a white solid. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=388.1 m/z.Activity: A

Example 92

3-bromo-4,5-dihydroisoxazole I-95a and I-95b were prepared in 2 stepsstarting with alkene formation from 1-(4-phenoxyphenyl)propan-1-oneusing Method 8 followed by cycloaddition using Method 1. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=347.7 m/z.Activity: A

Example 93

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96a and I-96b were preparedin 1 step from racemic compound I-14 and 5-hydroxypicolinic acid methylester according to the following procedure:3-bromo-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydroisoxazole (1.0 equiv),5-hydroxypicolinic acid methyl ester (1.2 equiv), and cesiumhydrogencarbonate (1.50 equiv) are suspended in N,N-dimethylforamide(0.32 M with respect to dihydroisoxazole. The mixture is then degassedwith argon after which it is heated to 130° C. for 4 h after which pointthere is only desired product and corresponding acid visible by LC/MS.The reaction is allowed to cool to room temperature and quenched bypouring into a solution of ammonium chloride in water (30% by weight,0.08 M with respect to dihydroisoxazole). The aqueous phase is extractedwith ethyl acetate (2×), dried over sodium sulfate, filtered andconcentrated to product a brown solid which could be recystallized fromabsolute ethanol to provide racemic3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96 that was isolated byfiltration as a white solid (25% yield). These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=383.8 m/z. Activity: A

Example 94

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid enantiomers I-97a and I-97bas a white solid which was isolated via vacuum filtration. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=369.3 m/z.Activity: A

Example 95

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-98a and I-98b were preparedin 1 step from racemic compound I-10 and3-(5-hydroxypyridin-2-yl)propanoic acid methyl ester using Method 5.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=418.1m/z. Activity: A

Example 96

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-98 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid I-99a and I-99b as a whitesolid which was isolated via vacuum filtration. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=402.8 m/z. Activity: A

Example 97

Racemic compound I-98 is dissolved in ammonia in methanol (7.0 M inmethanol, 0.02 M with respect to isoxazole). The reaction is sealed andallowed to stir at 23° C. for 72 h after which point the solvent andexcess ammonia are removed under a stream of nitrogen to provide a lightbrown solid which is triturated with hexanes to provide the desiredamide I-100a and I-100b as a white solid. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=404.5 m/z. Activity: A

Example 98

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-101a and I-101b were preparedin 1 step from racemic compound I-9 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=316.8 m/z. Activity: A

Example 99

3-bromo-4,5-dihydroisoxazole I-102a and I-102b were prepared in 2 stepsstarting with alkene formation from 1-(biphenyl-4-yl)ethanone usingMethod 8 followed by cycloaddition using Method 1. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=315.7 m/z. Activity: A

Example 100

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-103a and I-103b wereprepared in 1 step from racemic compound I-9 and 5-hydroxyprimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=318.7 m/z. Activity: A

Example 101

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-104a and I-104b wereprepared in 1 step from racemic compound I-102 and 5-hydroxyprimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=332.6 m/z. Activity: A

Example 102

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-97 (1.0 equiv) wasdissolved in methylene chloride (0.03 M with respect to isoxazole).Thionyl chloride is added (2.0 equiv) and the reaction was stirred for 1h at room temperature after which point it was concentrated under vacuumto a beige solid which was azeotroped with toluene (2×). The resultantsolid was redissolved in tetrahydrofuran (0.03 M with respect toisoxazole) after which glycine methyl ester (1.5 equiv) was addedfollowed by triethylamine (3.0 equiv). The reaction was stirred for 1 hat room temperature after which point it was transferred to a separatoryfunnel with excess water and ethyl acetate. The organic layer was thenwashed with saturated NaHCO₃ solution and brine, dried over magnesiumsulfate and concentrated under vacuum to provide crude material whichwas purified using flash silica gel chromatography (ethylacetate/hexanes) to provide amide I-105a and I-105b as a white solid.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M−H]−=437.5m/z. Activity: A

Example 103

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-105 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid I-106a and I-106b as awhite solid which was isolated via vacuum filtration. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=423.7 m/z.Activity: A

Example 104

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-107a and I-107b were preparedin using the analogous procedure as Example 102 except that methylaminewas used in the place of glycine methyl ester. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=382.5 m/z. Activity: A

Example 105

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-108a and I-108b were preparedin using the analogous procedure as Example 102 except thatdimethylamine was used in the place of glycine methyl ester. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+^(=396.6)m/z. Activity: B

Example 106

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-109a and I-109b were preparedin using the analogous procedure as Example 102 except that ethanolaminewas used in the place of glycine methyl ester. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=409.9 m/z. Activity: A

Example 107

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-67 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid I-110a and I-110b as awhite solid which was isolated via vacuum filtration. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=376.5 m/z.Activity: A

Example 108

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-67 is dissolved indimethylamine in methanol (2.0 M in tetrahydrofuran, 0.02 M with respectto isoxazole). The reaction is sealed and allowed to stir at 23° C. for72 h after which point the solvent and excess dimethylamine are removedunder a stream of nitrogen to provide a light brown solid which istriturated with hexanes to provide the desired amide I-111a and I-111bas a white solid. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=405.1 m/z. Activity: A

Example 109

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-112a and I-112b wereprepared in 1 step from racemic compound I-14 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. Activity: A

Example 110

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-113a and I-113b were preparedin 2 steps from racemic compound I-75 and 5-hydroxypicolinic acid methylester using Method 5 followed by hydrolysis under the same conditions asin example 94. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=380.7 m/z. Activity: A

Example 111

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-114a and I-114b were preparedfrom racemic compound I-113 by using the analogous procedure as Example102 except that methylamine (2.0M in tetrahydrofuran) was used in theplace of glycine methyl ester. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=396.4 m/z. Activity: A

Example 112

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-115a and I-115b were preparedfrom racemic compound I-113 by using the analogous procedure as Example102 except that ethylamine was used in the place of glycine methylester. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=411.1 m/z. Activity: A

Example 113

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-116a and I-116b were preparedfrom racemic compound I-113 by using the analogous procedure as Example102 except that trifluoroethylamine was used in the place of glycinemethyl ester. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M−H]−=461.7 m/z. Activity: B

Example 114

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-117a and I-117b were preparedfrom racemic compound I-113 by using the analogous procedure as Example102 except that hydroxylamine hydrochloride was used in the place ofglycine methyl ester. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+−=398.4 m/z. Activity: A

Example 115

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-105 is dissolved inammonia in methanol (7.0 M in methanol, 0.02 M with respect toisoxazole). The reaction is sealed and allowed to stir at 23° C. for 72h after which point the solvent and excess ammonia are removed under astream of nitrogen to provide a light brown solid which is trituratedwith hexanes to provide desired amide I-118a and I-118b as a whitesolid. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=325.1 m/z. Activity: B

Example 116

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-119a and I-119b wassynthesized in three steps starting with the conversion of4-bromo-3,3′-difluorobiphenyl to its corresponding alkene using Method 9followed by cycloaddition using Method 1 followed by displacement with5-hydroxyprimidine using Method 5. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=354.3 m/z. Activity: A

Example 117

3-bromo-4,5-dihydroisoxazole I-120a and I-120b were prepared in 2 stepsstarting with alkene formation from3-fluoro-4-(trifluoromethoxy)benzaldehyde using Method 8 followed bycycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=327.5 m/z. Activity: A

Example 118

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-121a and I-121b wereprepared in 1 step from racemic compound I-120 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=344.1 m/z. Activity: A

Example 119

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-122a and I-122b was preparedin 1 step from racemic compound I-120 and 5-hydroxypicolinic acid methylester using Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=400.3 m/z. Activity: A

Example 120

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-122 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid I-123a and I-123b as awhite solid which was isolated via vacuum filtration. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=386.3 m/z.Activity: A

Example 121

3-bromo-4,5-dihydroisoxazole I-124a and I-124b were prepared in 2 stepsstarting with alkene formation from3-chloro-4-(trifluoromethoxy)benzaldehyde using Method 8 followed bycycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=345.5 m/z. Activity: A

Example 122

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-125a and I-125b were preparedin 1 step from racemic compound I-124 and 5-hydroxypyrimidine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=359.7 m/z. Activity: A

Example 123

3-bromo-4,5-dihydroisoxazole I-126a and I-126b were prepared in 2 stepsstarting with alkene formation from2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde using Method 8 followedby cycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=305.6 m/z. Activity: A

Example 124

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-127a and I-127b were preparedin 1 step from racemic compound I-126 and 5-hydroxypyrimidine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=321.8 m/z. Activity: B

Example 125

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-128a and I-128b were preparedin analogous fashion to compound I-99 in Example 96 except that racemiccompound I-14 was used as starting material in place of racemic compoundI-10. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=398.2 m/z. Activity: A

Example 126

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-129a and I-129b wereprepared in 1 step from racemic compound I-75 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=339.8 m/z. Activity: A

Example 127

3-bromo-4,5-dihydroisoxazole I-130a and I-130b were prepared in 2 stepsstarting with the coupling between 4-phenoxyphenylboronic acid and2-bromo-3,3,3-trifluoroprop-1-ene as follows: A solution of toluene(0.25 M with respect to boronic acid) is cooled to 0° C. in a sealedtube after which point 2-bromo-3,3,3-trifluoroprop-1-ene (0.83 equiv) isadded followed by palladium tetrakis (2.5 mol %). The mixture is purgedwith Ar after which point a 2.0 M solution of sodium carbonate (1.5equiv) is added followed by the boronic acid (1.0 equiv) in methanol(1.0 M with respect to boronic acid). The mixture was purged a secondtime with Ar after which point it was heated to 70° C. in an oil bathfor 20 h. The reaction was allowed to cool after which it wastransferred to a separatory funnel with excess water and ethyl acetate,washed with a 2.0M solution of sodium carbonate (1×) and water (2×). Theorganic layer was dried and concentrated to provide a black oil whichwas purified by flash silica gel chromatography (ethyl acetate/hexanes)to provide the desired alkene as an oil in 35% yield which was converteddirectly to the desired racemic 3-bromo-4,5-dihydroisoxazole I-130 usingMethod 1. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=385.6 m/z. Activity: B

Example 128

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-131a and I-131b wereprepared in 1 step from racemic compound I-130 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=401.4 m/z. Activity: A

Example 129

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-132a and I-132b wereprepared in 1 step from racemic compound I-14 and2-(methylthio)pyrimidin-5-ol using Method 5 after2-(methylthio)pyrimidin-5-ol is first prepared from2-(methylthio)pyrimidin-5-ylboronic acid using Method 11. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=372.2 m/z.Activity: B

Example 130

Racemic 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-132 was dissolvedin methylene chloride (0.5 M with respect to isoxazole) after whichpoint m-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and thereaction was allowed to stir at room temperature for 1 h. After thereaction was determined to be complete by LC/MS, the solvent wasevaporated. The crude mixture was then redissolved in tert-butylmethylether (0.5 M) after which hexane was slowly added until a solidprecipitated. The solid was then collected via vacuum filtration andwashed with 1:1 hexanes/tert-butylmethyl ether to provide the desired3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-133a and I-133b as a whitesolid. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=404.1 m/z. Activity: A

Example 131

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-134a and I-134b were preparedin 1 step from racemic compound I-14 and 6-(methylthio)pyridin-3-olusing Method 5 after 6-(methylthio)pyridin-3-ol is first prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=372.4 m/z.Activity: A

Example 132

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-135a and I-135b were preparedfrom I-134 in analogous fashion to compound I-133 in example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=403.2 m/z.Activity: A

Example 133

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-136a and I-136b were preparedin 1 step from racemic compound I-14 and 5-fluoro-6-methoxypyridin-3-olusing Method 5 after 5-fluoro-6-methoxypyridin-3-ol is first preparedfrom 5-fluoro-6-methoxypyridin-3-boronic acid using Method 11. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=373.4 m/z.Activity: B

Example 134

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-137a and I-137b were preparedin 3 steps from 4-butoxybenzaldehyde using Method 8 followed bycycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazolewas reacted with 5-hydroxypicolinic acid methyl ester using Method 5.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=370.1m/z. Activity: A

Example 135

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-138a and I-138b were preparedin 1 step from compound I-137 using the analogous hydrolysis conditionsas in Example 94. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=357.7 m/z. Activity: A

Example 136

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-139a and I-139b wasprepared in 3 steps from 4-butoxybenzaldehyde using Method 8 followed bycycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazolewas reacted with 5-hydroxypyrimidine using Method 5. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=314.9 m/z. Activity: A

Example 137

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-140a and I-140b were preparedin 4 steps from 4-iso-propoxybenzaldehyde using Method 8 followed bycycloaddition using Method 1. The resulting bromo-4,5-dihydroisoxazolewas reacted with 5-hydroxypicolinic acid methyl ester using Method 5followed by hydrolysis using the analogous conditions as in Example 94These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=343.5m/z. Activity: A

Example 138

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-141a and I-141b wereprepared in 3 steps from 4-iso-propoxybenzaldehyde using Method 8followed by cycloaddition using Method 1. The resultingbromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=299.3 m/z. Activity: A

Example 139

3-bromo-4,5-dihydroisoxazole I-142a and I-142b were prepared in 3 stepsfrom 4-vinylphenyl acetate using the cycloaddition conditions inMethod 1. The resulting acetate is dissolved in tetrahydrofuran (1.0equiv, 0.18 M with respect to bromoisoxazole) and cooled to 0° C. in anice bath. Lithium hydroxide (3.0 equiv, 1.0 M in water) is added and thereaction is allowed to stir for 30 min after which point it wastransferred to a separatory funnel with excess water and ethyl acetate.The organic layer was extracted with saturated ammonium chloride, driedover sodium sulfate and evaporated to provide the desired phenol inquantitative yield which was used directly. The phenol (1.00 equiv) wasdissolved in acetonitrile (0.20 M with respect to starting material) andcooled to 0° C. in an ice bath. Propargyl bromide (2.0 equiv) was addedfollowed by cesium carbonate (3.0 equiv). The reaction was allowed tostir for 2 h after which it was quenched with saturated ammoniumchloride and transferred to a separatory funnel with excess water andethyl acetate. The organic layer was dried over sodium sulfate andevaporated to provide the desired racemic alkyne I-142 which waspurified by flash silica gel chromatography (ethyl acetate/hexanes) toprovide the desired racemic compound in 70% yield. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=279.7 m/z. Activity: A

Example 140

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-143a and I-143b wereprepared in 1 step from racemic compound I-142 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=296.5 m/z. Activity: B

Example 141

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-144a and I-144b were preparedin 1 step from racemic compound I-142 and 5-hydroxypicolinic acid methylester using Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=353.5 m/z. Activity: A

Example 142

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-145a and I-145b were preparedin 1 step from racemic compound I-144 using the analogous hydrolysisconditions as in Example 94. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=338.8 m/z. Activity: A

Example 143

3-phenoxy-4,5-dihydroisoxazole I-146a and I-146b were prepared in 1 stepfrom racemic compound I-61 using the analogous hydrolysis conditions asin Example 94. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=376.2 m/z. Activity: B

Example 144

3-phenoxy-4,5-dihydroisoxazole I-147a and I-147b were prepared in 1 stepfrom racemic compound I-62 using the analogous hydrolysis conditions asin Example 94. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=375.7 m/z. Activity: A

Example 145

3-bromo-4,5-dihydroisoxazole I-148a and I-148b were prepared in 1 stepfrom 1-bromo-4-vinylbenzene using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=350.5 m/z. Activity: A

Example 146

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-149a and I-149b were preparedin 1 step from racemic compound I-148 and 5-hydroxypicolinic acid methylester using Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M−H]−=378.4 m/z. Activity: A

Example 147

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-150a and I-150b were preparedin 1 step from racemic compound I-149 using the analogous hydrolysisconditions as in Example 94. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=362.6 m/z. Activity: A

Example 148

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-151a and I-151b were preparedin 1 step from racemic compound I-14 and 4-hydroxypicolinic acid methylester using Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=384.2 m/z. Activity: A

Example 149

Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-151 (1.0 equiv) wasdissolved in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide(8.0 equiv) was added. The reaction was allowed to stir at roomtemperature for 1 h after which point the tetrahydrofuran was removedunder a stream of nitrogen and the remaining solution was acidified topH<2 with 1N HCl to provide the desired acid I-152a and I-152b as awhite solid which was isolated via vacuum filtration. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=368.9 m/z.Activity: A

Example 150

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-153a and I-153b wereprepared in 2 steps 1-chloro-4-vinylbenzene using Method 1. Theresulting bromo-4,5-dihydroisoxazole was reacted with5-hydroxypyrimidine using Method 5. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=277.3 m/z. Activity: B

Example 151

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-154a and I-154b were preparedin 1 step from racemic compound I-75 and 6-(furan-3-yl)pyridin-3-olusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=406.3 m/z. Activity: A

Example 152

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-155a and I-155b were preparedfrom racemic acid I-110 according to the following procedure: in amicrowave reactor tube, acetyl hydrazide (1.0 equiv) and acid I-110 (1.0equiv) were dissolved in dry acetonitrile (0.1 M each).Polystyrene-supported triphenylphosphine (3.0 equiv) andtrichloroacetonitrile (2.0 equiv) were added, and the mixture was sealedand heated in a microwave reactor at 130° C. for 2 hours. After thispoint the reaction was determined to be incomplete by LC/MS such that1.5 additional equivalents of triphenylphosphine resin were addedfollowed by 1.0 additional equivalents of trichloroacetonitrile. Thevessel was resealed and heated for an additional 2 h at 130° C. Oncompletion, the concentrated reaction mixture was purified by flashsilica gel chromatography (hexanes/ethyl acetate) to provide the desiredracemic oxadiazole I-155. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M+H]+=415.5 m/z. Activity: A

Example 153

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-156a and I-156b were preparedusing the analogous procedure to Example 152 except that racemiccompound I-113 was used as the starting acid. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=422.0 m/z. Activity: A

Example 154

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-157a and I-157b were preparedusing the analogous procedure to Example 152 except that racemiccompound I-97 was used as the starting acid. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=407.2 m/z. Activity: A

Example 155

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-158a and I-158b were preparedfrom racemic acid I-113 according to the following procedure: acetylhydrazide (1.0 equiv) and acid I-113 (1.0 equiv) were dissolved in drydichloromethane (0.1 M each) and treated with EDC (1.05 equiv) and DMAP(0.10 equiv) after which the reaction mixture was allowed to stir at 23°C. for 6 h. After the reaction is complete it was diluted into aseparatory funnel with excess dichloromethane and water and the organiclayer was washed twice each with 0.5 M aqueous citric acid and saturatedaqueous sodium bicarbonate. The organic layer was dried over magnesiumsulfate and concentrated to a white solid. This solid was dissolved indry THF and 1.2 equiv Lawesson's reagent is added. The mixture wassealed in a tube and heated in a microwave reactor at 115° C. for 30min. The concentrated reaction mixture was purified by flash silica gelchromatography (hexanes/ethyl acetate) to provide the desired racemicthiadiazole I-158. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=438.2 m/z. Activity: A

Example 156

3-phenoxy-4,5-dihydroisoxazole I-159a and I-159b were prepared using theanalogous procedure to Example 152 except that racemic compound I-147was used as the starting acid. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=413.6 m/z. Activity: A

Example 157

3-phenoxy-4,5-dihydroisoxazole I-160a and I-160b were prepared using theanalogous procedure to Example 152 except that racemic compound I-146was used as the starting acid. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=414.4 m/z. Activity: A

Example 158

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-162a and I-162b were preparedaccording to the following procedure: Racemic dihydroisoxazole I-161 wasprepared in 1 step from compound I-14 and 6-bromopyridin-3-ol usingMethod 5. Compound I-161 placed in a microwave vial and then dissolvedin dioxane (0.02 M). 2-(tributylstannyl)thiazole and palladium tetrakiswere added and the reaction was purged with Argon. At this point thereaction was heated in the microwave reactor for 20 min after whichthere was no starting material by TLC analysis. The mixture isconcentrated and purified by flash silica gel chromatography(hexanes/ethyl acetate) to provide the desired racemic thiazole I-162 in50% yield. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M−H]−=407.3 m/z. Activity: A

Example 159

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-163a and I-163b were preparedusing the analogous procedure to Example 158 except that2-(tributylstannyl)oxazole was used in place of2-(tributylstannyl)thiazole. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=393.2 m/z. Activity: A

Example 160

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-164a and I-164b were preparedusing the analogous procedure to Example 158 except that racemiccompound I-75 was used in place of compound I-14 as starting material.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=423.4m/z. Activity: A

Example 161

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-165a and I-165b were preparedaccording to the following procedure: racemic dihydroisoxazole I-161 andsodium carbonate (10.0 equiv) were placed in a microwave vial. A 2:2:1mixture of toluene, ethanol and water (0.02 M with respect to I-161) wasadded followed by tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateboronicacid (1.5 equiv). The mixture was purged with Ar for 20 min after whichpoint palladium tetrakis (4 mol %) was added, the reaction was sealedand heated in an oil bath to 80° C. for 17 h. The reaction mixture wasthen allowed to cool after which it was transferred to a separatoryfunnel with excess ethyl acetate and water. The organic layer was washedwith water and saturated sodium chloride. The water layer was backextracted with ethyl acetate. The organic layers were combined, driedover sodium sulfate and concentrated to provide a crude oil that waspurified by flash silica gel chromatography (hexanes/ethyl acetate) toprovide the desired racemic pyrazole I-165 in 36% yield. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=392.4 m/z.Activity: C

Example 162

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-166a and I-166b wereprepared in 1 step from racemic compound I and 5-hydroxypyrimidine usingMethod 5. [M−H]−=241.5 m/z. Activity: B

Example 163

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-167a and I-167b were preparedin analogous fashion to compound I-135 in example 132 except thatracemic compound I-75 was used as the bromo-isoxazole starting material.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=417.3m/z. Activity: A

Example 164

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-168a and I-168b wereprepared in 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using thecycloaddition conditions from Method 1. The resultingbromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine toprovide racemic compound I-168 using Method 5. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=309.8 m/z. Activity: B

Example 165

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-169a and I-169b were preparedin 3 steps from 1-(trifluoromethyl)-4-vinylbenzene using thecycloaddition conditions from Method 1. The resultingbromo-4,5-dihydroisoxazole was reacted with 6-(methylthio)pyridin-3-ol(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11)using Method 5 followed by oxidation under analogous conditions toExample 130. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=387.2 m/z. Activity: A

Example 166

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-170a and I-170b were preparedin 3 steps from 1-(trifluoromethyl)-4-vinylbenzene using thecycloaddition conditions from Method 5. The resultingbromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acidmethyl ester using Method 5 followed by hydrolysis using the analogousconditions as in example 94. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=353.0 m/z. Activity: A

Example 167

1-(4,5-dihydroisoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acid I-171aand I-171b were prepared using the analogous procedure to Example 35except that racemic compound I-75 was used as the startingbromo-isoxazole and 1H-1,2,4-triazole-3-carboxylic acid methyl ester asthe nucleophile Additionally, at some point during the course of thereaction or workup, the ester hydrolyzed to the corresponding acid.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M−H]−=356.6m/z. Activity: C

Example 168

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-172a and I-172b were preparedin 1 step from racemic compound I-75 and pyrazolo[1,5-a]pyridin-2-olusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=378.1 m/z. Activity: C

Example 169

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-173a and I-173b were preparedusing the analogous procedure as Example 161 except that tert-butyl2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylatewas used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=390.6m/z. Activity: A

Example 170

3-phenoxy-4,5-dihydroisoxazole I-174a and I-174b were prepared in 1 stepfrom racemic compound I-14 and 3-(1H-tetrazol-5-yl)phenol using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=392.3 m/z. Activity: B

Example 171

3-phenoxy-4,5-dihydroisoxazole I-175a and I-175b were prepared in 1 stepfrom racemic compound I-14 and 4-(1H-tetrazol-5-yl)phenol using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=391.6 m/z. Activity: B

Example 172

3-phenoxy-4,5-dihydroisoxazole I-176a and I-176b were prepared in 2steps from racemic compound I-14. Bromo-4,5-dihydroisoxazole I-14 wasreacted with 3-hydroxybenzoic acid methyl ester using Method 5 followedby hydroysis using the analogous conditions as in example 94.[M+H]+=368.0 m/z. Activity: C

Example 173

3-phenoxy-4,5-dihydroisoxazole I-177a and I-177b were prepared in 2steps from racemic compound I-14. Bromo-4,5-dihydroisoxazole I-14 wasreacted with 4-hydroxybenzoic acid methyl ester using Method 5 followedby hydroysis using the analogous conditions as in Example 94. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=368.0 m/z.Activity: B

Example 174

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-178a and I-178b were preparedin 2 steps from racemic compound I-14 and 5-hydroxypicolinonitrile usingMethod 5 after 5-hydroxypicolinonitrile was prepared from5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile usingMethod 11. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=350.0 m/z. Activity: B

Example 175

3-bromo-4,5-dihydroisoxazole I-179a and I-179b were prepared in 1 stepfrom 1-pentyl-4-vinylbenzene using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=283.6 m/z. Activity: A

Example 176

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-180a and I-180b wereprepared in 1 step from racemic compound I-179 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=298.7 m/z. Activity: A

Example 177

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-181a and I-181b were preparedin 2 steps from racemic compound I-179 by first reacting I-179 with6-(methylthio)pyridin-3-ol (synthesized from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=375.4 m/z.Activity: A

Example 178

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-182a and I-182b were preparedin 2 steps from racemic compound I-14 by first reacting I-14 with6-(ethylthio)pyridin-3-ol (synthesized from6-(ethylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=417.1 m/z.Activity: A

Example 179

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-183a and I-183b were preparedin 2 steps from racemic compound I-14 by first reacting I-14 with6-(cyclopentylthio)pyridin-3-ol (synthesized from6-(cyclopentylthio)pyridin-3-ylboronic acid using Method 11) usingMethod followed by oxidation under analogous conditions to example 130.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=456.8m/z. Activity: B

Example 180

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-184a and I-184b were preparedin 2 steps from racemic compound I-14 by first reacting I-14 with6-(iso-butylthio)pyridin-3-ol (synthesized from6-(iso-butylthio)pyridin-3-ylboronic acid using Method 11) using Method5 followed by oxidation under analogous conditions to Example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=444.7 m/z.Activity: B

Example 181

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-185a and I-185b were preparedusing the analogous procedure to Example 178 except that racemiccompound I-75 was used in place of compound I-75 as starting materialand 2-(tributylstannyl)oxazole was used in place of2-(tributylstannyl)thiazole (as in Example 158). These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=407.2 m/z. Activity: A

Example 182

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-186a and I-186b were preparedusing the analogous procedure as Example 161 except that 2-furylboronicacid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=392.2m/z. Activity: A

Example 183

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-187a and I-187b were preparedusing the analogous procedure as Example 161 except that5-methylfuran-2-ylboronic acid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=406.3m/z. Activity: A

Example 184

The enantioners of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-188a andI-188b were prepared using the analogous procedure as Example 161 exceptthat 5-boronofuran-2-carboxylic acid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=435.5m/z. Activity: C

Example 185

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-189a and I-189b were preparedusing the analogous procedure as Example 161 except that1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wasused in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=406.2m/z. Activity: A

Example 186

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-190a and I-190b were preparedusing the analogous procedure as Example 161 except that1,3-dimethyl-1H-pyrazol-5-ylboronic acid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=419.4m/z. Activity: A

Example 187

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-191a and I-191b were preparedusing the analogous procedure as Example 161 except that1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylboronic acid was used inplace of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=473.3m/z. Activity: C

Example 188

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-192a and I-192b were preparedusing the analogous procedure as Example 161 except that1H-pyrazol-5-ylboronic acid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=391.4m/z. Activity: A

Example 189

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-193a and I-193b were preparedusing the analogous procedure as Example 161 except that5-boronothiophene-2-carboxylic acid was used in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=450.6m/z. Activity: B

Example 190

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-194a and I-194b were preparedaccording to the following procedure: racemic dihydroisoxazole I-161,tribasic potassium phosphate (3.0 equiv),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.2 equiv),and the palladium catalyst (10 mol %) were placed in a microwave vial.Dioxane (0.1 M with respect to I-161) was added and the mixture waspurged with Ar for 20 min after which point the reaction was sealed andheated in an oil bath to 85° C. for 17 h. The reaction mixture was thenallowed to cool after which it was transferred to a separatory funnelwith excess ethyl acetate and water. The organic layer was washed withwater and saturated sodium chloride. The water layer was back extractedwith ethyl acetate. The organic layers were combined, dried over sodiumsulfate and concentrated to provide a crude oil that was purified byflash silica gel chromatography (hexanes/ethyl acetate) to provide thedesired racemic pyrazole I-194 in <5% yield. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=392.2 m/z. Activity: A

Example 191

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-195a and I-195b were preparedaccording to the following procedure: racemic dihydroisoxazole I-178(1.0 equiv) was dissolved in N,N-dimethylforamide (0.1 M with respect toisoxazole) after which ammonium chloride (3.1 equiv) and sodium azide(1.5 equiv) were added. The reaction was then heated in an oil bath to120° C. for 4 h after which point it the reaction was transferred to aseparatory funnel with excess ethyl acetate and water. The organic layerwas washed with water and saturated sodium chloride, dried over sodiumsulfate and concentrated to provide a crude oil that was purified byflash silica gel chromatography (hexanes/ethyl acetate) to provide thedesired racemic tetrazole I-195. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=393.2 m/z. Activity: A

Example 192

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-196a and I-196b were preparedin 2 steps from racemic compound I-75 by first reacting I-75 with6-(ethylthio)pyridin-3-ol (prepared from6-(ethylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=431.3 m/z.Activity: A

Example 193

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-197a and I-197b were preparedin 2 steps from racemic compound I-10 by first reacting I-10 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=411.4 m/z.Activity: A

Example 194

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-198a and I-198b were preparedin 1 step from racemic compound I-75 and 6-(1H-pyrazol-1-yl)pyridin-3-olusing Method 5 after 6-(1H-pyrazol-1-yl)pyridin-3-ol was synthesizedfrom2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineusing Method 11. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=405.3 m/z. Activity: A

Example 195

3-(phenoxy)-4,5-dihydroisoxazole I-199a and I-199b were prepared in 1step from racemic compound I-14 and3-(3-methyl-1,2,4-oxadiazol-5-yl)phenol using Method 5. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=406.3 m/z.Activity: C

Example 196

3-(Phenoxy)-4,5-dihydroisoxazole I-200a and I-200b were prepared in 1step from racemic compound I-14 and 4-(2-methyl-2H-tetrazol-5-yl)phenolusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=406.4 m/z. Activity: B

Example 197

3-(phenoxy)-4,5-dihydroisoxazole I-201a and I-201b were prepared in 1step from racemic compound I-14 and 4-(1,3,4-oxadiazol-2-yl)phenol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=392.2 m/z. Activity: A

Example 198

3-bromo-4,5-dihydroisoxazole I-202a and I-202b were prepared in 2 stepsaccording to the following procedure: 4-vinylbenzoyl chloride (1.0equiv) was dissolved in methylene chloride (0.375 M with respect tostyrene) after which morpholine (3.0 equiv) is added. The reaction isallowed to stir at room temperature for 14 h during which time a whiteprecipitate began to form. The reaction was then transferred to aseparatory funnel with excess water and methylene chloride. The organiclayer was washed with water (1×), 1N HCl (1×), saturated sodiumbicarbonate (1×) and brine (1×) after which point it was dried oversodium sulfate and concentrated to provide a yellow oil. This crudematerial was then directly used to form the desired racemicbromoisoxazole using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=338.7 m/z. Activity: B

Example 199

3-bromo-4,5-dihydroisoxazole I-203a and I-203b were prepared using theanalogous procedure as Example 198 except that dimethyl amine intetrahydrofuran (2.0 M) was used in place of morpholine. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=299.3 m/z.Activity: A

Example 200

3-bromo-4,5-dihydroisoxazole I-204a and I-204b were prepared using theanalogous procedure as Example 198 except that methyl amine intetrahydrofuran (2.0 M) was used in place of morpholine. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=282.6 m/z.Activity: B

Example 201

3-bromo-4,5-dihydroisoxazole I-205a and I-205b were prepared in 2 stepsaccording to the following procedure: 4-vinylbenzene-1-sulfonyl chloride(1.0 equiv) was dissolved in methylene chloride (0.50 M with respect tostyrene) after which morpholine (3.0 equiv) is added. The reaction isallowed to stir at room temperature 90 min after which point it wastransferred to a separatory funnel with excess water and methylenechloride. The organic layer was washed with water (1×), 1N HCl (1×),saturated sodium bicarbonate (1×) and brine (1×) after which point itwas dried over sodium sulfate and concentrated to provide a yellow oil.This crude material was then directly used to form the desired racemicbromoisoxazole using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=374.6 m/z. Activity: A

Example 202

3-bromo-4,5-dihydroisoxazole I-206a and I-206b were prepared using theanalogous procedure as Example 201 except that dimethyl amine in THF(2.0 M) was used in place of morpholine. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=332.6 m/z. Activity: A

Example 203

3-bromo-4,5-dihydroisoxazole I-207a and I-207b were prepared using theanalogous procedure as Example 201 except that methyl amine in THF (2.0M) was used in place of morpholine. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=318.6 m/z. Activity: A

Example 204

3-bromo-4,5-dihydroisoxazole I-208a and I-208b were prepared using theanalogous procedure as Example 198 except that piperidine was used inplace of morpholine. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=339.3 m/z. Activity: A

Example 205

3-bromo-4,5-dihydroisoxazole I-209a and I-209b were prepared using theanalogous procedure as Example 198 except that pyrrolidine was used inplace of morpholine. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=322.6 m/z. Activity: A

Example 206

3-bromo-4,5-dihydroisoxazole I-210a and I-210b were prepared using theanalogous procedure as Example 201 except that piperidine was used inplace of morpholine. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=472.6 m/z. Activity: A

Example 207

3-bromo-4,5-dihydroisoxazole I-211a and I-211b were prepared using theanalogous procedure as Example 201 except that pyrrolidine was used inplace of morpholine. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=358.6 m/z. Activity: A

Example 208

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-212a and I-212b were preparedin 2 steps from racemic compound I-203 by first reacting I-203 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=390.4 m/z.Activity: B

Example 209

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-213a and I-213b were preparedin 2 steps from racemic compound I-202 by first reacting I-202 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=426.2 m/z.Activity: A

Example 210

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-214a and I-214b were preparedin 2 steps from racemic compound I-21 by first reacting I-21 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=352.2 m/z.Activity: A

Example 211

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-215a and I-215b were preparedin 2 steps compound from racemic compound I-21.Bromo-4,5-dihydroisoxazole I-21 was reacted with 5-hydroxy picolinicacid methyl ester using Method 5 followed by hydrolysis using theanalogous conditions as in example 94. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=418.3 m/z. Activity: B

Example 212

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-216a and I-216b were preparedin 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using thecycloaddition conditions from Method 1. The resultingbromo-4,5-dihydroisoxazole was reacted with 2-bromo-5-hydroxypyridineusing Method 5 to provide racemic compound I-216. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=389.1 m/z. Activity: B

Example 213

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-217a and I-217b were preparedusing the analogous procedure as Example 212 except that3-(1,3,4-oxadiazol-2-yl)phenol was used in place of2-bromo-5-hydroxypyridine. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M+H]+=376.4 m/z. Activity: A

Example 214

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-218a and I-218b were preparedusing the analogous procedure as Example 161 except that1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wasused in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=404.8m/z. Activity: A

Example 215

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-219a and I-219b were preparedusing the analogous procedure as Example 161 except that1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wasused in place of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateand racemic bromopyridine I-216 was used as the starting material ratherthan I-161. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=390.3 m/z. Activity: A

Example 216

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-220a and I-220b were preparedaccording to the following procedure: acid I-97 (1.0 equiv) wasdissolved in methylene chloride (0.08 M). Oxalyl chloride (1.5 equiv wasadded) followed by the addition of 1 drop of N,N-dimethylforamide. Thereaction was stirred at room temperature for 20 min after which it wasconcentrated under vacuum. The crude material was then redissolved inmethylene chloride after which methanesulfonamide (1.2 equiv), DMAP (10mol %) and triethylamine (1.5 equiv) were added. After 3 h, the reactionwas determined to be complete by LC/MS analysis. The reaction mixturewas then transferred to a separatory funnel with excess ethyl acetateand water. The organic layer was washed with 1N HCl and brine, driveover sodium sulfate and concentrated under vacuum to provide the desiredsulfonamide. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=446.1 m/z. Activity: A

Example 217

3-(phenoxy)-4,5-dihydroisoxazole I-221a and I-221b were prepared in 1step from racemic compound I-14 and 3-(4H-1,2,4-triazol-4-yl)phenolusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=392.0 m/z. Activity: C

Example 218

3-(phenoxy)-4,5-dihydroisoxazole I-222a and I-222b were prepared in 3steps according to the following procedures: 3-hydroxy benzoic acidmethyl ester is reacted with racemic bromoisoxazole I-75 using Method 5.The resulting methyl ester (1.0 equiv) is dissolved in methanol (0.08 M)after which hydrazine (50 equiv, 50% by weight in water) is added andthe reaction is allowed to stir for 14 h. The reaction mixture is thenconcentrated under vacuum and used directly in the next step.Triethylorthoacetate (8.0 equiv) is added and the reaction is sealed andheated to reflux for 14 h. The reaction is then transferred to aseparatory funnel with excess ethyl acetate and water. The organic layerwas washed water and brine, drive over sodium sulfate and concentratedunder vacuum to provide crude material which was purified using flashsilica gel chromatography (gradient ethyl acetate/hexanes) to providethe desired racemic oxadiazole I-222. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=420.5 m/z. Activity: A

Example 219

3-(phenoxy)-4,5-dihydroisoxazole I-223a and I-223b were prepared usingthe analogous procedure as Example 218 except that racemic compound I-15was used in place of compound I-75 as starting material. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=406.5 m/z.Activity: A

Example 220

3-(phenoxy)-4,5-dihydroisoxazole I-224a and I-224b were prepared in 3steps according to the following procedures: 3-fluoro-5-hydroxybenzoicacid methyl ester is reacted with racemic bromoisoxazole I-14 usingMethod 5. The resulting methyl ester (1.0 equiv) is dissolved inmethanol (0.08 M) after which hydrazine (50 equiv, 50% by weight inwater) is added and the reaction is allowed to stir for 14 h. Thereaction mixture is then concentrated under vacuum and used directly inthe next step. Triethylorthoacetate (8.0 equiv) is added and thereaction is sealed and heated to reflux for 14 h. The reaction is thentransferred to a separatory funnel with excess ethyl acetate and water.The organic layer was washed water and brine, drive over sodium sulfateand concentrated under vacuum to provide crude material which waspurified using flash silica gel chromatography (gradient ethylacetate/hexanes) to provide the desired racemic oxadiazole I-224. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=424.5 m/z.Activity: A

Example 221

3-(phenoxy)-4,5-dihydroisoxazole I-225a and I-225b were prepared usingthe analogous procedure as Example 220 except that triethylorthoformatewas used in place of triethylorthoacetate to form the desiredoxadiazole. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=410.3 m/z. Activity: A

Example 222

3-(phenoxy)-4,5-dihydroisoxazole I-226a and I-226b were prepared usingthe analogous procedure as Example 220 except that4-fluoro-5-hydroxybenzoic acid methyl ester was used in place of3-fluoro-5-hydroxybenzoic acid methyl ester in the first step. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=410.4 m/z.Activity: A

Example 223

3-(phenoxy)-4,5-dihydroisoxazole I-227a and I-227b were prepared usingthe analogous procedure as Example 222 except that racemic compound I-75was used in place of compound I-14 as starting material. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=424.2 m/z.Activity: A

Example 224

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-228a and I-228b were preparedin 3 steps according to the following procedures: 5-hydroxynicotinicacid methyl ester is reacted with racemic bromoisoxazole I-75 usingMethod 5. The resulting methyl ester (1.0 equiv) is dissolved inmethanol (0.08 M) after which hydrazine (50 equiv, 50% by weight inwater) is added and the reaction is allowed to stir for 14 h. Thereaction mixture is then concentrated under vacuum and used directly inthe next step. Triethylorthoformate (8.0 equiv) is added and thereaction is sealed and heated to reflux for 14 h. The reaction is thentransferred to a separatory funnel with excess ethyl acetate and water.The organic layer was washed water and brine, drive over sodium sulfateand concentrated under vacuum to provide crude material which waspurified using flash silica gel chromatography (gradient ethylacetate/hexanes) to provide the desired racemic oxadiazole I-228. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=407.5 m/z.Activity: A

Example 225

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-229a and I-229b were preparedusing the analogous procedure as Example 224 except thattriethylorthoacetate was used in place of triethylorthoformate to formthe desired oxadiazole. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M+H]+=422.0 m/z. Activity: A

Example 226

3-(phenoxy)-4,5-dihydroisoxazole I-230a and I-230b were prepared usingthe analogous procedure as Example 224 except that racemic compound I-14was used in place of compound 75 as starting material. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=393.2 m/z.Activity: A

Example 227

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-231a and I-231b were preparedin 3 steps according to the following procedures: 5-hydroxynicotinicacid methyl ester is reacted with racemic bromoisoxazole I-75 usingMethod 5. The resulting methyl ester (1.0 equiv) is dissolved inmethanol (0.08 M) after which hydrazine (50 equiv, 50% by weight inwater) is added and the reaction is allowed to stir for 14 h. Thereaction mixture is then concentrated under vacuum and used directly inthe next step. The hydrazide is dissolved in dioxane (0.12 M withrespect to hydrazide). N,N-Carbonydiimidazole (1.2 equiv) is added andthe reaction is sealed and heated to reflux for 4 h. The reaction isthen transferred to a separatory funnel with excess ethyl acetate andwater. The organic layer was washed water and brine, drive over sodiumsulfate and concentrated under vacuum to provide crude material whichwas purified using flash silica gel chromatography (gradientmethanol/dichloromethane) to provide the desired racemic1,3,4-oxadiazol-2(3H)-one I-231. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=423.4 m/z. Activity: B

Example 228

3-(phenoxy)-4,5-dihydroisoxazole I-232a and I-232b were prepared in 1step from racemic compound I-75 and 4-(1,3,4-oxadiazol-2-yl)phenol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=406.5 m/z. Activity: A

Example 229

3-(phenoxy)-4,5-dihydroisoxazole I-233a and I-233b were prepared in 1step from racemic compound I-75 and3-hydroxy-N,N-dimethylbenzenesulfonamide using Method 5. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=445.4 m/z.Activity: C

Example 230

3-(phenoxy)-4,5-dihydroisoxazole I-234a and I-234b were prepared in 1step from racemic compound I-75 and 4-(methylsulfonyl)phenol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=415.6 m/z. Activity: B

Example 231

3-(phenoxy)-4,5-dihydroisoxazole I-235a and I-235b were prepared in 1step from racemic compound I-75 and4-hydroxy-N,N-dimethylbenzenesulfonamide using Method 5. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=445.3 m/z.Activity: C

Example 232

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-236a and I-236b were preparedin 3 steps according to the following procedures: racemicdihydroisoxazole I-161 (1.0 equiv) was dissolved in N,N-dimethylforamide(0.1 M). Copper iodide (1.0 equiv) was added followed bytrimethylsilylacetylene (3.0 equiv) and N,N-diisopropyl ethylamine (2.0equiv). Palladium tetrakis (15 mol %) was added and the reaction wassealed and heated in a microwave reactor at 100° C. for 1 h. Thereaction was allowed to cool after which it was transferred to aseparatory funnel with ethyl acetate and water. The organic layer wasthen washed with water and brine, dried over sodium sulfate,concentrated and purified by flash silica gel chromatography (gradientethyl acetate/hexanes). The TMS group was then deprotected by dissolvingthis material in methanol (0.07 M) and adding potassium carbonate (3.0equiv). After stirring for 4 h at room temperature, the reaction wastransferred a separatory funnel with ethyl acetate and water. Theorganic layer was then washed with water and brine, dried over sodiumsulfate, concentrated and purified by flash silica gel chromatography(gradient ethyl acetate/hexanes). The resulting alkyne was thenconverted to the desired triazole by first dissolving it in neattrimethyl silylazide (80 equiv), purging the reaction mixture with Argonand heating in a microwave reactor to 110° C. for 3 h. After anadditional 4 h of heating the reaction was 60% complete by LC/MSanalysis at which point it was concentrated and purified directly byflash silica gel chromatography (gradient methanol/methylene chloride)to provide the desired racemic triazole I-236. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=392.9 m/z. Activity: A

Example 233

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-237a and I-237b were preparedin 2 steps from racemic compound I-148 by first reacting I-148 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to example 130. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=396.6 m/z.Activity: A

Example 234

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-238a and I-238b were preparedin 2 steps from 1-(trifluoromethyl)-4-vinylbenzene using thecycloaddition conditions from Method 1. The resultingbromo-4,5-dihydroisoxazole was reacted with 6-(methylthio)pyridin-3-ol(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11)using Method 5 to provide compound I-238. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=355.3 m/z. Activity: A

Example 235

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-240a and I-240b were preparedin 2 steps according to the following procedures: 6-bromopyridin-3-ol(1.0 equiv) and sodium carbonate (10.0 equiv) are added to a microwavevial. Toluene, ethanol, and water (0.16 M, 2:2:1 v/v) are added followedby 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.5 equiv). The mixture is purged with argon for 15 min followed by theaddition of palladium tetrakis (4 mol %). The reaction tube is thencovered with aluminum foil and heated to 80° C. in an oil bath for 17 h.After cooling the reaction was transferred to a separatory funnel withexcess water and ethyl acetate. The organic layer was then washed withwater (1×), saturated ammonium chloride (1×) and brine (1×). The aqueouslayers were combined and washed with ethyl acetate (1×). The organiclayers were then combined, dried over sodium sulfate, concentrated andpurified using flash silica gel chromatography (gradientmethanol/methylene chloride) to provide6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol I-239 as a white solid. Thiscompound is then reacted with racemic 3-bromo-4,5-dihydroisoxazole I-75using Method 5 to provide the desired racemic compound I-240. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=419.3 m/z.Activity: A

Example 236

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-241a and I-241b were preparedusing the analogous procedure as Example 235 except that1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole wasused in place of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole asthe boronoate in the first step. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=406.2 m/z. Activity: A

Example 237

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-242a and I-242b were preparedusing the analogous procedure as Example 188 except that racemiccompound I-75 was used in place of compound I-14 as starting material.These compounds can be separated using chiral HPLC methods known in theart. For example, see chiral HPLC Method disclosed herein. [M+H]+=406.3m/z. Activity: A

Example 238

2-(4,5-dihydroisoxazol-3-ylamino)ethanol I-243a and I-243b were preparedin 2 steps according to the following procedures: racemic3-bromo-4,5-dihydroisoxazole I-10 (1.0 equiv) was dissolved in n-butanol(0.57 M) followed by the addition of(tert-butyldimethylsilyloxy)methanamine (1.2 equiv) and sodium carbonate(2.5 equiv). The reaction was sealed and heated in a microwave reactionfor 1 h at 150° C. after which point there was very little productformation by LC/MS analysis. The reaction was then resealed and heatedfor an additional 24 h at 120° C. in the microwave after which it wastransferred to a separatory funnel with excess water andtert-butylmethyl ether. The aqueous layer was washed withtert-butylmethyl ether (2×) and the combined organic layers were washedwith brine, dried over magnesium sulfate and concentrate to provide aorange solid that was purified using flash silica gel chromatography(gradient ethyl acetate/hexane) to provide the desired silyl ether. Thiscompound (1.0 equiv) was then dissolved in methanol (0.02 M) and cooledto 0° C. in an ice bath. Acetyl chloride (50 equiv) was added dropwiseafter which the reaction was allowed to stir for min at 0° C. Thesolvent and remaining acetyl chloride was then removed under a stream ofnitrogen after which the crude material was purified by flash silica gelchromatography (gradient ethyl acetate/methanol) to provide racemicI-243. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=300.2 m/z. Activity: B

Example 239

2-((4,5-dihydroisoxazol-3-yl)(methyl)amino)acetic acid I-244a and I-244bwere prepared in 2 steps according to the following procedure: racemic3-bromo-4,5-dihydroisoxazole I-10 was converted to the corresponding3-amino-4,5-dihydroisoxazole by reacting it with sarcosine ethyl esterunder the same conditions as in Example 238. The ethyl ester was thenhydrolyzed using the analogous conditions as in Example 119 to provide amixture of racemic I-244. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M−H]−=327.5 m/z. Activity: B

Example 240

2-(4,5-dihydroisoxazol-3-ylamino)alcohol I-245a and I-245b were preparedin 1 step according to the following procedure: racemic3-bromo-4,5-dihydroisoxazole I-10 (1.0 equiv) was dissolved in n-butanol(0.64 M) followed by the addition of (S)-2-amino-1-phenylethanol (1.2equiv) and sodium carbonate (2.5 equiv). The reaction is the sealed andheated in an oil bath to 120° C. for 18 h after which it allowed to cooland then transferred to a separatory funnel with excess water andtert-butylmethyl ether. The aqueous layer was washed withtert-butylmethyl ether (2×) and the combined organic layers were washedwith brine, dried over magnesium sulfate and concentrate to provide aorange solid that was purified using flash silica gel chromatography(gradient toluene/hexanes to toluene/ethyl acetate) to provide racemicI-245 as a white solid. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M+H]+=374.20 m/z. Activity: C

Example 241

2-(4,5-dihydroisoxazol-3-ylamino)alcohol I-246a and I-246b were preparedusing the analogous procedure as Example 240 except that racemic3-bromo-4,5-dihydroisoxazole I-14 was used in place of3-bromo-4,5-dihydroisoxazole I-10 as starting material and that(R)-2-amino-1-phenylethanol was used in place of(S)-2-amino-1-phenylethanol. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=365.6 m/z. Activity: C

Example 242

3-(phenylthio)-4,5-dihydroisoxazole I-248a and I-248b were prepared in 2steps according to the following procedure: N,N-dibromoformaldoxime (1.0equiv) was dissolved in tetrahydrofuran. Thiophenol (2.0 equiv) wasadded followed by sodium hydride (1.98 equiv). After stirring for 1 h,the reaction is concentrated and purified by flash silica gelchromatography (gradient ethyl acetate/hexanes) to provide the desireddiphenyl hydroxycarbonimidodithioate I-247. The dithioate (1.0 equiv) isthen redissolved in acetonitrile (1.0 M) followed by the addition of1-(trifluoromethoxy)-4-vinylbenzene (2.4 equiv), silver nitrate (1.0equiv) and potassium carbonate (1.0 equiv). The reaction was allowed tostir for 3d at room temperature after which point it was concentratedand purified by flash silica gel chromatography (gradient ethylacetate/hexanes) to provide racemic 3-(phenylthio)-4,5-dihydroisoxazoleI-248. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=339.9 m/z. Activity: C

Example 243

3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249a and I-249b were preparedby the oxidation of racemic 3-(phenylthio)-4,5-dihydroisoxazole I-248.3-(Phenylthio)-4,5-dihydroisoxazole I-248 (1.0 equiv) was dissolved inethanol (0.15 M) followed by the addition of excess hydrogen peroxide inwater (30% by weight, >50 equiv) and 1N HCl (0.29 M). The reaction wasstirred at room temperature for 14 h after which it was transferred to aseparatory funnel with excess water and methylene chloride. The waterlayer was extracted with methylene chloride (1×), dried over magnesiumsulfate, and concentrated to provide crude product that wasrecrystallized from hexanes to provide the desired racemic3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=355.5 m/z. Activity: C

Example 244

3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250a and I-250b were preparedby the oxidation of racemic 3-(phenylsulfinyl)-4,5-dihydroisoxazoleI-249. 3-(Phenylsulfinyl)-4,5-dihydroisoxazole I-249 is dissolved inmethylene chloride (0.03 M). m-Chloroperbenzoic acid (77% by weight,2.95 equiv) are added in two portions and the reaction is allowed tostir at room temperature for 14 h after which it is transferred to aseparatory funnel with excess water and methylene chloride. The organiclayer is washed with saturated sodium bicarbonate (2×), dried overmagnesium sulfate, and concentrated to provide crude solid that isrecrystallized from methylene chloride/hexanes to provide the desiredracemic 3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=371.7 m/z.Activity: C

Example 245

3-(phenylthio)-4,5-dihydroisoxazole I-251a and I-251b were preparedusing the analogous procedure as Example 242 except that methyl4-mercaptobenzoate was used in place of thiophenol to form the requisitehydroxycarbonimidodithioate. The resulting methyl ester cycloadduct wasthen hydrolyzed using the analogous conditions as in example 94 toprovide racemic 3-(phenylthio)-4,5-dihydroisoxazole I-251. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=384.1 m/z.Activity: C

Example 246

N-ethyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-253a and I-253b wereprepared in 2 steps according to the following procedure:N,N-dibromoformaldoxime (1.05 equiv) was dissolved in acetonitrile.Thiophenol (1.0 equiv) and N-ethyl aniline (1.0 equiv) were added andthe reaction was allowed to stir at room temperature for 2.5 h afterwhich point triethylamine (5.0 equiv) is added. After stirring for 1 h,the solids that have now precipitated out of the reaction are filteredand the filtrate is concentrated and purified directly by flash silicagel chromatography (gradient ethyl acetate/hexanes with 1%triethylamine) to provide the desired carbamimidothioate I-252. Thecarbamimidothioate (1.0 equiv) is then redissolved in acetonitrile (1.0M) followed by the addition of 1-(trifluoromethoxy)-4-vinylbenzene (2.4equiv), silver nitrate (1.07 equiv) and potassium carbonate (1.17equiv). The reaction was allowed to stir for 1d at room temperatureafter which point it was purified by flash silica gel chromatography(gradient ethyl acetate/hexanes with 1% triethylamine) to provideracemic 4,5-dihydroisoxazol-3-amine I-253. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=352.1 m/z. Activity: C

Example 247

N-methyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-255a and I-255b wereprepared in 3 steps according to the following procedure:N,N-dibromoformaldoxime (1.05 equiv) was dissolved in acetonitrile.Thiophenol (1.0 equiv) and 4-(methylamino)benzoic acid methyl ester (1.0equiv) were added after which point triethylamine (3.0 equiv) is addedin 3 portions. After stirring for 3 h, the reaction was transferred to aseparatory funnel with excess water and methylene chloride. The organiclayer was washed with 1N HCl (2×), dried over magnesium sulfate,concentrated and purified using flash silica gel chromatography(gradient ethyl acetate/hexanes with 0.5% triethyl amine followed bygradient methanol/methylene chloride with 0.5% triethyl amine) toprovide the desired carbamimidothioate I-254. The carbamimidothioate(1.0 equiv) is then redissolved in acetonitrile (1.0 M) followed by theaddition of 1-(trifluoromethoxy)-4-vinylbenzene (1.8 equiv), silvernitrate (2.3 equiv) and potassium carbonate (2.1 equiv). The reactionwas allowed to stir for 1d at room temperature after which point it waspurified by flash silica gel chromatography (gradient ethylacetate/hexanes with 0.5% triethylamine followed by gradientmethanol/methylene chloride with 0.5% triethylamine. The resultingracemic methyl ester cycloadduct was then hydrolyzed using the analogousconditions as in Example 94 to provide racemicN-methyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-255. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M+H]+=381.5 m/z. Activity: C

Example 248

3-(pyrrolidin-1-yl)-4,5-dihydroisoxazole I-256a and I-256b were preparedusing the analogous procedure as Example 238 except that pyrrolidine wasused in place of (S)-2-amino-1-phenylethanol. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+^(=310.3) m/z. Activity: C

Example 249

3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yloxy)-4,5-dihydroisoxazoleI-257a and I-257b were prepared in 1 step from compound I-10 and1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol using Method 5. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=403.7 m/z.Activity: B

Example 250

3-(phenoxy)-4,5-dihydroisoxazole I-258a and I-258b were prepared in 1step from racemic compound I-14 and 3-(1,3,4-oxadiazol-2-yl)phenol usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=392.4 m/z. Activity: A

Example 251

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-259a and I-259b were preparedusing the analogous procedure to Example 152 except that racemiccompound I-170 was used as the starting acid. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M+H]+=390.7 m/z. Activity: A

Example 252

4,5-dihydroisoxazol-3-yl acetate I-260a and I-260b were prepared in 3steps according to the following procedures: racemic bromoisoxazole I-10was (1.0 equiv) was dissolved in tetrahydrofuran (1.0 M). 1N Sodiumhydroxide solution is added (4.0 equiv) followed by allyl alcohol (45equiv). The reaction was sealed and heated to 60° C. for 3 h. Thereaction mixture was allowed to cool and then transferred to aseparatory funnel with excess water and ethyl acetate. The organic layerwas washed water and brine, drive over sodium sulfate and concentratedunder vacuum to provide crude material which was purified using flashsilica gel chromatography (gradient ethyl acetate/hexanes). Theresulting allyl ether (1.0 equiv) was then dissolved in tetrahydrofuran(0.2 M). Formic acid (5.0 equiv) was added followed by palladiumtetrakis (10 mol %) after which the reaction was allowed to stir for 2 hat room temperature. The reaction mixture was transferred to aseparatory funnel with excess water and ethyl acetate. The organic layerwas washed with saturated sodium bicarbonate and brine, dried oversodium sulfate and purified using flash silica gel chromatography(gradient ethyl acetate/hexanes). The resulting isoxazolidin-3-one (1.0equiv) was dissolved in methylene chloride (0.3 M) after whichN,N-dimethyamino pyridine (1.0 equiv) and acetic anhydride (1.0 equiv)were added. After stirring at room temperature for 14 h, the reactionwas transferred to a separatory funnel with excess water and ethylacetate. The organic layer was washed with 1N HCl and brine, dried oversodium sulfate and concentrated to provide the desired racemic acetateI-260. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=297.8 m/z. Activity: D

Example 253

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-261a and I-261b were preparedin 1 step from racemic compound I-75 and 6-(methylthio)pyridin-3-olusing Method 5 after 6-(methylthio)pyridin-3-ol is first prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=386.2 m/z.Activity: A

Example 254 Inhibition of Human FAAH

Human FAAH Preparation: COS-7 cells were split the day before, 1:5 into150 mm x mm cell culture dishes (Corning Inc., Cat. No. 430599).Transient transfection took place at 30-40% confluency according toFuGENE 6 Transfection Reagent (Roche, Cat. No. 11814 443 001).

Transfection Procedure: The FuGENE transfection 6 reagent (45 uL) wasadded to 1410 μL of media (DMEM, serum free without pen/strep) in a 15mL conical tube and incubated at room temp for 5 minutes, followed bythe addition of FAAH plasmid DNA (15 μg) (OriGene Cat. No. TC119221,Genbank Accession No. NM_(—)001441.1, 0.67 ug/uL) and a furtherincubation of 15 minutes at room temperature. The resulting solution wasadded into one dish of 30-40% confluent COS-7 cells in a drop-wisemanner. The COS-7 cell dish was subsequently incubated for 48 hours. Thecells are then harvested.

Harvest procedure: Media was aspirated from the dishes and the cellsrinsed with 10 mL PBS. The PBS was removed and 3 mL of PBS added to thedish. The dish was scraped to resuspend the cells, and the subsequentcell suspension collected into a 15 mL conical tube. The cells werepelleted by centrifugation at 1200 rpm for 5 minutes in a bench topcentrifuge. PBS was removed and the cell pellet snap frozen in liquidnitrogen and stored at −80° C.

COS-7 cells —FAAH purification:

-   -   (1) Fractionation: Frozen cell pellets from transient        transfections were thawed on ice and resuspended in 12.5 mM        Hepes pH 8.0, 100 mM NaCl, 1 mM EDTA (10 mL/0.2 g cell pellet).        The pellets were dounce homogenized and then sonicated to        produce cell extract. The cell extract was subsequently        centrifuged at 1000 g to remove cellular debris. The pellet was        discarded and the supernatant centrifuged at 13,000 g for 20        minutes. The pellet contained membrane bound FAAH. The        supernatant was discarded and the pellet resolubilized.    -   (2) Re-solubilization: The fraction of interest, (13,000 g,        membrane fraction) was re-suspended in 2.3 mL re-suspension        buffer (20 mM Hepes pH 7.8, 10% v/v Glycerol, 1 mM EDTA, 1%        Triton X-100) and the sample incubated on ice for 1 hour and        then centrifuged to remove any particulate matter. The        supernatant containing solubilized human FAAH was aliquoted and        snap frozen in liquid nitrogen and stored at −80° C. until use.    -   (3) Characterization: Protein Concentration determined by        Bradford assay.        -   SDS gel and Western blot to confirm presence of FAAH        -   FAAH activity assay        -   K_(m) determination-96-well assay        -   Linear dependence—96-well assay        -   Standard compound Ki determination—384-well assay

Human FAAH assay; Experimental Protocol: A 0.1 mg/mL Human FAAH solutionwas made up in FAAH reaction buffer, and 24 ul pipeted into a 384 wellplate. To this was added 1 μL of a 3 fold serially diluted inhibitorfrom a DMSO stock solution. The FAAH solution and inhibitor wereincubated for 30 minutes at room temperature. The FAAH reaction wasinitiated by the addition of 25 μL of 40 μM AMC Arachidonoyl Amide inFAAH reaction buffer, yielding a final reaction human FAAH preparationconcentration of 0.05 mg/ml and AMC-Arachidonoyl substrate concentrationof 20 μM, reaction volume 50 μL. The reaction was allowed to proceed for4 hours at room temperature. The reaction was stopped by the addition of25 μL 12 μM a-ketoheterocycle (Cayman Chemicals, catalogue #10435). Themicrotiter plate was read in the envision plate reader.

The raw fluorescence was plotted on the y axis and the inhibitorconcentration on the x axis to give a dose response inhibition curve.The data was fitted to a single site competitive inhibition equation,fixing the Km for the human enzyme to 12 μM and 9 μM respectively.

Other assays which can be used to determine the inhibition of FAAH bythe compounds of the present invention include: (1) a fluorescence-basedassay for fatty acid amide hydrolase compatible with high-throughputscreening as described in Manjunath et al., Analytical Biochemistry(2005) 343:143-151; and (2) a high-throughput screening for thediscovery of inhibitors of fatty acid amide hydrolase using amicrosome-based fluorescent assay. Wang et al., Biomolecular Screening(2006) 1-9.

Example 255 Evidence for Covalent Complex Formation between Serine-241of FAAH and Isoxazolines

Treatment of rat FAAH protein with the active site-directed irreversibleinhibitor methoxy arachidonyl fluorophosphonate results in a crystalstructure wherein methoxy arachidonyl phosphonate is covalently bound tothe side chain of Ser-241 (Bracey et al., Science (2002) 298:1793-1796).

Based on this data, it is hypothesized that the isoxazoline compounds ofthe present invention form covalent complexes with the nucleophilic sidechain of Ser-241. This hypothesis is consistent with the kinetic data,with the proposed binding involving nucleophilic attack of theisoxazoline electrophile by the active site Ser-241, resulting in theelimination of the leaving group from the cytosolic port, and thesubsequent formation of a covalent enzyme-isoxazoline adduct. Recoveryof activity would subsequently involve a deacylation reaction, whichwould occur inefficiently, if at all, for the covalentenzyme-isoxazoline adduct.

Recovery of activity experiments were performed via a jump dilutionmethod which involved rapidly diluting the enzyme-inhibitor complex5-fold below its apparent Ki, and measuring activity as a function oftime. Little or no enzyme activity was regained over a period of twohours, indicating essentially irreversible inhibition, or a very slowlyhydrolysable complex, supporting the above hypothesis.

Other Embodiments

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A compound of formula (I):

or a pharmaceutically acceptable form thereof, wherein: each of R^(a),R^(b), and R^(c) independently is selected from H, C₁₋₁₀ alkyl and C₁₋₁₀perhaloalkyl, R^(d) is the group -L-Z, and Z is selected from C₆₋₁₄aryl; L is a covalent bond or a divalent C₁₋₆ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen, sulfur or nitrogen atoms; G isselected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion; and each R^(e) is selected from C₁₋₁₀ alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 memberedheterocyclyl and 5-14 membered heteroaryl; each R^(f) attached to anitrogen atom is, independently, selected from —H, C₁₋₁₀ alkyl, or anamino protecting group; or R^(e) and R^(f) are joined to form an 3-14membered heterocyclyl ring or an 5-14 membered heteroaryl ring.
 2. Thecompound according to claim 1, wherein L is a covalent bond or L is adivalent C₁₋₆ hydrocarbon group, wherein one, two or three methyleneunits of L are replaced with one or more oxygen atoms.
 3. The compoundaccording to claim 2, wherein L is a covalent bond.
 4. The compoundaccording to claim 2, wherein L is an unsubstituted divalent C₁₋₆hydrocarbon group, wherein one methylene unit of L is replaced with anoxygen atom.
 5. The compound claim 2, wherein L is —O—.
 6. The compoundaccording to claim 1, wherein R^(a), R^(b), and R^(c) independently isselected from —H, C₁₋₃alkyl and C₁₋₃ perhaloalkyl.
 7. The compoundaccording to claim 6, wherein each R^(a), R^(b), and R^(c) isindependently selected from —H, —CH₃ and —CF₃.
 8. The compound accordingto claim 7, wherein R^(a) and R^(b) are —H and R^(c) is selected from—CH₃ and —CF₃.
 9. The compound according to claim 7, wherein R^(b) andR^(c) are —H and R^(a) is selected from —CH₃ and —CF₃.
 10. The compoundaccording to claim 7, wherein each of R^(a), R^(b), and R^(c) is —H. 11.The compound according to claim 1, wherein Z is phenyl.
 12. The compoundaccording to claim 11, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof; wherein z is 0, 1, 2, 3,4 or 5; and each R¹⁵ is independently selected from fluoro (—F), bromo(—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—OR¹⁶, —ON(R¹⁸)₂, —N(R¹⁸)₂, —N(R¹⁸)₃ ⁺X⁻, —N(OR⁷)R¹⁸, —SH, —SR¹⁶,—SSR¹⁷, —C(═O)R¹⁶, —CO₂H, —CHO, —C(OR¹⁷)₂, —CO₂R¹⁶, —OC(═O)R¹⁶,—OCO₂R¹⁶, —C(═O)N(R¹⁸)₂, —OC(═O)N(R¹⁸)₂, —NR¹⁸C(═O)R¹⁶, —NR¹⁸CO₂R¹⁶,NR¹⁸C(═O)N(R¹⁸)₂, —C(═NR¹⁸)R¹⁶, —C(═NR¹⁸)OR¹⁶, —OC(═NR¹⁸)R¹⁶,—OC(═NR¹⁸)OR¹⁶, —C(═NR¹⁸)N(R¹⁸)₂, —OC(═NR¹⁸)N(R¹⁸)₂,—NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, —C(═O)NR¹⁸SO₂R¹⁶, —NR¹⁸SO₂R¹⁶, —SO₂N(R¹⁸)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —OSO₂R¹⁶, —S(═O)R¹⁶, —OS(═O)R¹⁶, —Si(R¹⁶)₃,—OSi(R¹⁶)₃—C(═S)N(R¹⁸)₂, —C(═O)SR¹⁶, —C(═S)SR₁₆, —SC(S)SR¹⁶—P(═O)₂R¹⁶,—OP(═O)₂R¹⁶, P(═O)(R¹⁶)₂, —OP(═O)(R¹⁶)₂, —OP(═O)(OR⁷)₂, —P(═O)₂N(R¹⁸)₂,—OP(═O)₂N(R¹⁸)₂, —P(═O)(NR¹⁸)₂, —OP(═O)(NR¹⁸)₂, —NR¹⁸P(═O)(OR¹⁷)₂,—NR¹⁸P(═O)(NR¹⁸)₂, —P(R¹⁷)₂, —P(R¹⁷)₃, —OP(R⁷)₂, —OP(R¹⁷)₃, —B(OR¹⁷)₂,—BR¹⁶(OR¹⁷), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; or two vicinal R¹⁵groups are replaced with the group —O(C(R²)₂)₁₋₂O— wherein each R² isindependently —H, C₁₋₆ alkyl or halogen; each instance of R¹⁶ is,independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; eachinstance of R¹⁸ is, independently, selected from hydrogen, —OH, —OR¹⁶,—N(R¹⁷)₂, —CN, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶, —SO₂R¹⁶,—C(═NR¹⁷)OR¹⁶, —C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂, —SO₂R¹⁷, —SO₂OR¹⁷, —SOR¹⁶,—C(═S)N(R¹⁷)₂, —C(═O)SR¹⁷, —C(═S)SR¹⁷, —P(═O)₂R¹⁶, —P(═O)(R¹⁶)₂,—P(═O)₂N(R¹⁷)₂, —P(═O)(NR¹⁷)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R¹⁷ groups attached toan N atom are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; each instance of R¹⁷is, independently, selected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR¹⁷ groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; eachinstance of R¹⁹ is, independently, selected from halogen, —CN, —NO₂,—N₃, —SO₂H, —SO₃H, —OH, —OR²⁰, —ON(R²¹)₂, —N(R²¹)₂, —N(R²¹)₃ ⁺X⁻,—N(OR²⁰)R²¹, —SH, —SR²⁰, —SSR²⁰, —C(═O)R²⁰, —CO₂H, —CO₂R²⁰, —OC(═O)R²⁰,—OCO₂R²⁰, —C(═O)N(R²¹)₂, —OC(═O)N(R²¹)₂, —NR²¹C(═O)R²⁰, —NR²¹CO₂R²⁰,—NR²¹C(═O)N(R²¹)₂, —C(═NR²¹)OR²⁰, —OC(═NR²¹)R²⁰, OC(═NR²¹)OR²⁰,—C(═NR²¹)N(R²¹)₂, —OC(═NR²¹)N(R²¹)₂, —NR²¹C(═NR²¹)N(R²¹)₂, —NR²¹SO₂R²⁰,—SO₂N(R²¹)₂, —SO₂R²⁰, —SO₂OR²⁰, —OSO₂R²⁰, —S(═O)R²⁰, —Si(R²⁰)₃,—OSi(R²⁰)₃, —C(═S)N(R²¹)₂, —C(═O)SR²⁰, —C(═S)SR²⁰, —SC(═S)SR²⁰,—P(═O)₂R²⁰, —P(═O)(R²⁰)₂, —OP(═O)(R²⁰)₂, —OP(═O)(OR²⁰)₂, C₁₋₆alkyl, C₁₋₆perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R²²groups, or two geminal R¹⁹ substituents can be joined to form ═O or ═S;each instance of R²⁰ is, independently, selected from C₁₋₅alkyl, C₁₋₅perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R²² groups; eachinstance of R²¹ is, independently, selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or twoR²¹ groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R²² groups; and eachinstance of R²² is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆alkyl)X, —NH₃X, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆alkyl), —SO₂N(C₁₋₁₆alkyl)₂, —SO₂NH(C₁₋₆alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂,C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R²² substituents can be joined to form ═O or═S; wherein X⁻ is a counterion.
 13. The compound according to claim 12,wherein R¹⁵ is selected from fluoro (—F), bromo (—Br), chloro (—Cl), andiodo (—I), —OR¹⁶, —C(═O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂, C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups.
 14. The compound according to claim 12, wherein z is 1 or
 2. 15.The compound according to claim 14, wherein z is
 1. 16. The compoundaccording to claim 15, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof.
 17. The compoundaccording to claim 16, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof; wherein R¹⁶ is,independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups.
 18. Thecompound according to claim 17, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof.
 19. The compoundaccording to claim 17, wherein the compound is formula:

or a pharmaceutically acceptable form thereof.
 20. The compoundaccording to claim 16, wherein the compound is formula:

or a pharmaceutically acceptable form thereof.
 21. The compoundaccording to claim 14, wherein z is
 2. 22. The compound according toclaim 21, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof.
 23. The compoundaccording to claim 22, wherein the compound is of the formulae:

or a pharmaceutically acceptable form thereof.
 24. The compoundaccording to claim 1, wherein G is selected from —Cl, —Br, —I, —OR^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), and—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion.
 25. The compoundaccording to claim 24, wherein G is —OR^(e).
 26. The compound accordingto claim 25, wherein R^(e) is C₆₋₁₄ aryl.
 27. The compound according toclaim 26, wherein R^(e) is phenyl.
 28. The compound according to claim27, wherein R^(e) is a monosubstituted phenyl.
 29. The compoundaccording to claim 27, wherein R^(e) is a phenyl group of the formula:

wherein: x is 0, 1, 2, 3, 4 or 5, and each R^(h) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(i), —ON(R^(k))₂, —N(R^(k))₂,—N(R^(k))₃ ⁺X⁻, —N(OR^(j))R^(k), —SH, —SR^(i), —SSR^(j), —C(═O)R^(i),—CO₂H, —CHO, —CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂,—OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═NR^(k)) R^(i), —C(═NR^(k))OR^(i),—OC(═NR^(k))R^(i), —OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂,—OC(═NR^(k))N(R^(k))₂, —NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(k)SO₂R^(i), —SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i),—S(═O)R^(i), —OS(═O)R^(i), —Si(R^(i))₃, —OSi(R^(i))₃—C(═S)N(R^(k))₂,—C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i), —P(═O)₂R^(i), —OP(═O)₂R^(i),—P(═O)(R^(i))₂, —OP(═O)(R^(i))₂, —OP(═O)(OR)₂, —P(═O)₂N(R^(k))₂,—OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂, —OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR)₂,—NR^(k)P(═O)(NR^(k))₂, —P(R)₂, —P(R^(j))₃, —OP(R^(i))₂, —OP(R^(j))₃,—B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(i) is, independently, selected from CO₁₀ alkyl, CO₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; each instance of R^(k) is, independently, selected fromhydrogen, —OH, —OR^(i), —N(R)₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂,—CO₂R^(i), —SO₂R^(i), —C(═NR^(j))OR^(i), —C(═NR^(j))N(R^(j))₂,—SO₂N(R)₂, —SO₂R^(j), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂,—C(═O)SR^(j), —C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂,—P(═O)₂N(R^(j))₂, —P(═O)(NR^(j))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(j)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(j) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two Rj groups attached to an N atom are joined to form a3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; each instance of R^(m) is, independently, selected from fluoro(—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂, —N(R^(n))₃ ⁺X⁻,—N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o), —CO₂H, —CO₂R^(o),—OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂, —OC(═O)N(R^(n))₂,—NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o), —NR^(n)C(═O)N(R^(n))₂,—C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o), —OC(═NR^(n))OR^(o),—C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂, —NR^(n)C(═NR^(n))N(R^(n))₂,—NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o), —SO₂OR^(o), —OSO₂R^(o),—S(═O)R^(o), —Si(R^(o))₃, —OSi(R^(o))₃, —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups, or twogeminal R^(m) substituents can be joined to form ═O or ═S; each instanceof R^(o) is, independently, selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; eachinstance of R^(n) is, independently, selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or twoR^(n) groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; andeach instance of R^(p) is, independently, fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),—N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₁₆ alkyl), —OC(═O)(C₁₋₆ alkyl),—CO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),—NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₁₆ alkyl, —SO₂OC₁₋₁₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₄ aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; or twogeminal R^(p) substituents can be joined to form ═O or ═S; wherein X⁻ isa counterion.
 30. The compound according to claim 29, wherein R^(h) isselected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —OH, —OR^(i), —SR^(i), —N(R^(k))₂, —N(R^(k))₃ ⁺X⁻,—C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i), —OCO₂R^(i),—C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂Ri, C₁₋₁₀ alkyl, C₆ aryl, and 5-6 memberedheteroaryl, wherein each alkyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3 or 4 R^(m) groups; and wherein X⁻ is acounterion.
 31. The compound according to claim 30, wherein R^(h) isselected from —C(═O)R^(i), —CO₂H, —SO₂R^(i), and 5-membered heteroarylindependently substituted with 0 or 1 R^(m) groups.
 32. The compoundaccording to claim 31, wherein the 5-membered heteroaryl is selectedfrom pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl.
 33. The compound according to claim 29,wherein the phenyl group is a monosubstituted phenyl group of any one ofthe formulae:


34. The compound according to claim 29, wherein the phenyl group is adisubstituted phenyl group of any one of the formulae:


35. The compound according to claim 25, wherein G is —OR^(e) selectedfrom:


36. The compound according to claim 25, wherein R^(e) is 5-14 memberedheteroaryl.
 37. The compound according to claim 36 wherein R^(e) is a6-membered heteroaryl.
 38. The compound according to claim 37, whereinR^(e) is a pyrindinyl group.
 39. The compound according to claim 38,wherein R^(e) is a monosubstituted pyrindinyl group.
 40. The compoundaccording to claim 38, wherein R^(e) is a 3-pyridinyl group.
 41. Thecompound according to claim 38, wherein R^(e) is a pyrindinyl group ofthe formula:

wherein x is 0, 1, 2, 3 or 4, and each R^(h) is, independently, selectedfrom fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂,—N₃, —SO₂H, —SO₃H, —OH, —OR^(i), —ON(R^(k))₂, —N(R^(k))₂, —N(R^(k))₃⁺X⁻, —N(OR^(j))R^(k), —SH, —SR^(i), —SSR^(j), —C(═O)R^(i), —CO₂H, —CHO,—CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂,—NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂,—C(═NR^(k))R^(i), —C(═NR^(k))OR^(i), —OC(═NR^(k))R^(i),—OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —OC(═NR^(k))N(R^(k))₂,—NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i), —S(═O)R^(i),—OS(═O)R^(i), —Si(R^(i))₃, —OSi(R^(i))₃—C(═S)N(R^(k))₂, —C(═O)SR^(i),—C(═S)SR^(i), —SC(S)SR^(i), —P(═O)₂R^(i), —OP(═O)₂R^(i), —P(═O)(R^(i))₂,—OP(═O)(R^(i))₂, —OP(═O)(OR)₂, —P(═O)₂N(R^(k))₂, —OP(═O)₂N(R^(k))₂,—P(═O)(NR^(k))₂, —OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR)₂,—NR^(k)P(═O)(NR^(k))₂, —P(R)₂, —P(R^(j))₃, —OP(R^(j))₂, —OP(R^(j))₃,—B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(i) is, independently, selected from C₁₋₁₀ alkyl, CO₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; each instance of R^(k) is, independently, selected fromhydrogen, —OH, —OR^(i), —N(R)₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂,—CO₂R^(i), —SO₂R^(i), —C(═NR^(j))OR^(j), —C(═NR^(j))N(R^(j))₂,—SO₂N(R)₂, —SO₂R^(i), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂,—C(═O)SR^(j), —C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂,—P(═O)₂N(R^(j))₂, —P(═O)(NR^(j))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(j)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(j) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(j) groups attached to an N atom are joined to forma 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; each instance of R^(m) is, independently, selected from fluoro(—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂, —N(R^(n))₃ ⁺X⁻,—N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o), —CO₂H, —CO₂R^(o),—OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂, —OC(═O)N(R^(n))₂,—NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o), —NR^(n)C(═O)N(R^(n))₂,—C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o), —OC(═NR^(n))OR^(o),—C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂, —NR^(n)C(═NR^(n))N(R^(n))₂,—NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o), —SO₂OR^(o), —OSO₂R^(o),—S(═O)R^(o), —Si(R^(o))₃, —OSi(R^(o))₃, —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₅ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups, or twogeminal R^(m) substituents can be joined to form ═O or ═S; each instanceof R^(o) is, independently, selected from C₁₋₆alkyl, C₁₋₆ perhaloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; eachinstance of R^(n) is, independently, selected from hydrogen, C₁₋₆alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or twoR^(n) groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; andeach instance of R^(p) is, independently, fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),—N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl),—C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl),—OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl),—NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl),—NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂,—OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₁₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂,C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl, 5-14 memberedheteroaryl; or two geminal R^(p) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.
 42. The compound according to claim41, wherein R^(h) is selected from fluoro (—F), bromo (—Br), chloro(—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i), —N(R^(k))₂,—N(R^(k))₃ ⁺X⁻, —C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i), —OCO₂R^(i),—C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂R^(i), C₁₋₁₀ alkyl, C₆ aryl, and 5-6 memberedheteroaryl, wherein each alkyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3 or 4 R^(m) groups; and wherein X⁻ is acounterion.
 43. The compound according to claim 42, wherein R^(h) isselected from —C(═O)R^(i), —CO₂H, —SO₂R^(i), and 5-membered heteroarylindependently substituted with 0 or 1 R^(m) groups.
 44. The compoundaccording to claim 43, wherein the 5-membered heteroaryl is selectedfrom pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl.
 45. The compound according to claim 41,wherein the pyridinyl group is a 3-pyridinyl group of the formulae:


46. The compound according to claim 25, wherein G is —OR^(e) selectedfrom:


47. The compound according to claim 1, wherein the compound issubstantially enantiomerically pure.
 48. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable formthereof, and a pharmaceutically acceptable excipient.
 49. A method oftreating an FAAH-mediated condition comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable form thereof.
 50. The methodaccording to claim 49, wherein the FAAH-mediated condition is selectedfrom a painful condition, an inflammatory condition, an immune disorder,a disorder of the central nervous system, a metabolic disorder, acardiac disorder and glaucoma.
 51. The method according to claim 50,wherein the FAAH-mediated condition is a painful condition selected fromneuropathic pain, central pain, deafferentiation pain, chronic pain,post-operative pain, pre-operative pain, nociceptive pain, acute pain,non-inflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, pain associated with medical procedures, painresulting from pruritus, painful bladder syndrome, pain associated withpremenstrual dysphoric disorder, pain associated with premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with drawal symptoms from drugaddiction, joint pain, arthritic pain, lumbosacral pain,musculo-skeletal pain, headache, migraine, muscle ache, lower back pain,neck pain, toothache dental/maxillofacial pain and visceral pain. 52.The method according to claim 50, wherein the FAAH-mediated condition isan inflammatory condition or an immune disorder.
 53. The methodaccording to claim 52, wherein the inflammatory condition or immunedisorder is a gastrointestinal disorder.
 54. The method according toclaim 52, wherein the inflammatory condition or immune disorder is askin condition.
 55. The method according to claim 50, wherein theFAAH-mediated condition is a disorder of the central nervous systemselected from neurotoxicity and/or neurotrauma, stroke, multiplesclerosis, spinal cord injury, epilepsy, a mental disorder, a sleepcondition, a movement disorder, nausea and/or emesis, amyotrophiclateral sclerosis, Alzheimer's disease and drug addiction
 56. The methodaccording to claim 50, wherein the FAAH-mediated condition is ametabolic disorder selected from a wasting condition or anobesity-related condition or complication thereof.
 57. The methodaccording to claim 50, wherein the FAAH-mediated condition is a cardiacdisorder selected from hypertension, circulatory shock, myocardialreperfusion injury and atherosclerosis.
 58. The method according toclaim 50, wherein the FAAH-mediated condition is glaucoma.